Mutations in the TrkA gene cause a related disorder, HSAN IV, which produces a phenotype similar to HSAN V. xref These TrkA gene mutations result in defective binding of NGF to TrkA and, as a result, the inhibition of NGF-induced TrkA phosphorylation and downstream signaling cascades. xref

In cultured rodent DRG neurons, for example, Nav1.7 activation is increased via Erk1/2 signaling, and activation of p38 MAPK can directly phosphorylate Nav1.8 leading to an increase in Nav1.8 current density in DRG neurons. xref , xref However, whether these changes to sodium channel activation properties occur downstream of NGF-TrkA signaling, or as part of other signaling pathways, was not explored in these studies.

While numerous studies have demonstrated a role for NGF-TrkA signaling in the modulation of nociceptive ion channel activity, there is also evidence that NGF-p75NTR signaling can contribute to sensory neuron excitability. xref , xref - xref For example, NGF-mediated activation of p75NTR has been shown to increase ceramide levels in a TrkA-independent manner in cell culture, and studies in rodents have shown that ceramide likely mediates NGF-induced sensitization of isolated sensory neurons in vitro and possibly NGF-induced pain-related behaviors in vivo. xref , xref , xref

While numerous studies have demonstrated a role for NGF-TrkA signaling in the modulation of nociceptive ion channel activity, there is also evidence that NGF-p75NTR signaling can contribute to sensory neuron excitability. xref , xref - xref For example, NGF-mediated activation of p75NTR has been shown to increase ceramide levels in a TrkA-independent manner in cell culture, and studies in rodents have shown that ceramide likely mediates NGF-induced sensitization of isolated sensory neurons in vitro and possibly NGF-induced pain-related behaviors in vivo. xref , xref , xref

Figures  xref A,B show that GSB-106 induced the transient and similar to BDNF moderate TrkB Tyr 706/707 phosphorylation within 10 min, followed by a decrease at 60 min, whilst BDNF caused substantial Tyr 706/707 phosphorylation at 60 min.

Figures  xref A,B show that GSB-106 induced the transient and similar to BDNF moderate TrkB Tyr 706/707 phosphorylation within 10 min, followed by a decrease at 60 min, whilst BDNF caused substantial Tyr 706/707 phosphorylation at 60 min.

Next, we determined the role of upstream components of TrkB/PI3K/Akt cascade in BAD phosphorylation, induced by BDNF and GSB-106.

Next, we determined the role of upstream components of TrkB/PI3K/Akt cascade in BAD phosphorylation, induced by BDNF and GSB-106.

Altogether, our data shows that SFK inhibitor PP2 preferentially reduced both BDNF- and GSB-106-mediated phosphorylation of Tyr 816 compared to Tyr 706/707 and Tyr 515 under given experimental conditions.

Altogether, our data shows that SFK inhibitor PP2 preferentially reduced both BDNF- and GSB-106-mediated phosphorylation of Tyr 816 compared to Tyr 706/707 and Tyr 515 under given experimental conditions.

BDNF binding to TrkB evokes receptor dimerization and initial phosphorylation of tyrosine residues within the autoregulatory loop of the kinase domain (human TrkB Tyr 706/707 ) followed by autophosphorylation of cytoplasmic conserved tyrosine residues (human TrkB Tyr 515 , Tyr 816 ) xref .

BDNF binding to TrkB evokes receptor dimerization and initial phosphorylation of tyrosine residues within the autoregulatory loop of the kinase domain (human TrkB Tyr 706/707 ) followed by autophosphorylation of cytoplasmic conserved tyrosine residues (human TrkB Tyr 515 , Tyr 816 ) xref .

Thus, TrkB and Akt are likely required for BDNF- and GSB-106-stimulated BAD activation in serum withdrawn SH-SY5Y cells.

Thus, TrkB and Akt are likely required for BDNF- and GSB-106-stimulated BAD activation in serum withdrawn SH-SY5Y cells.

It has been reported that BDNF activation of TrkB resulted in increased SFKs activity, promotion of protein complex formation consisting of TrkB and SFKs—Fyn and Src in vitro.

It has been reported that BDNF activation of TrkB resulted in increased SFKs activity, promotion of protein complex formation consisting of TrkB and SFKs—Fyn and Src in vitro.

Pretreatment of cells with a pharmacological Trk inhibitor K252a led to suppression of BDNF- or GSB-106-induced activation of Erk1/2 and Akt (Fig.  xref D), thus suggesting that the pro-survival signaling evoked by GSB-106 in serum withdrawn SH-SY5Y cells requires TrkB activation.

Pretreatment of cells with a pharmacological Trk inhibitor K252a led to suppression of BDNF- or GSB-106-induced activation of Erk1/2 and Akt (Fig.  xref D), thus suggesting that the pro-survival signaling evoked by GSB-106 in serum withdrawn SH-SY5Y cells requires TrkB activation.

Pretreatment of cells with a pharmacological Trk inhibitor K252a led to suppression of BDNF- or GSB-106-induced activation of Erk1/2 and Akt (Fig.  xref D), thus suggesting that the pro-survival signaling evoked by GSB-106 in serum withdrawn SH-SY5Y cells requires TrkB activation.

Pretreatment of cells with a pharmacological Trk inhibitor K252a led to suppression of BDNF- or GSB-106-induced activation of Erk1/2 and Akt (Fig.  xref D), thus suggesting that the pro-survival signaling evoked by GSB-106 in serum withdrawn SH-SY5Y cells requires TrkB activation.

The BDNF-TrkB.

The precise mechanism of how LASP1 promotes PTEN ubiquitination still remains elusive xref .

In another study, the heat shock-like protein Clusterin was shown to increase AKT2 activity and promote the motility of both normal and malignant prostate cells via an inhibitory activity on PTEN-S380 phosphorylation and consequent inactivation of PTEN xref .

Another study demonstrated that phosphorylation of PTEN on tyrosine 240 by FGFR2 promotes chromatin binding through an interaction with Ki-67, which facilitates the recruitment of RAD51 to promote DNA repair xref . xref summarises these novel functions and signalling axes of nuclear PTEN.

It was reported that PTEN could dephosphorylate PGK1, a glycolytic enzyme and protein kinase with a tumorigenic role in glioblastoma xref .

Dephosphorylation of PGK1 by PTEN was found to inhibit its activity, downstream glycolytic functions, and glioblastoma cell proliferation xref , thereby presenting another mechanism in which PTEN functions as a tumour suppressor.

The present study is a prospective, single-blinded, randomized, placebo-controlled cross-over study to investigate the effects of intravenously administered LPS (Escherichia coli O113, 2 ng/kg) on tryptophan and kynurenine metabolites over 48 h and their association with interleukin-6 (IL-6) and C-reactive protein (CRP).

Also, the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular-signal-regulated kinase (ERK) were stimulated by S100A8, which had an analogous effect to the lipopolysaccharide (LPS) treatment ( xref C–E).

Also, the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular-signal-regulated kinase (ERK) were stimulated by S100A8, which had an analogous effect to the lipopolysaccharide (LPS) treatment ( xref C–E).

Notably, the effect of EZH2 inhibition-induced inactivation of mTOR complexes was not completely reversed after Deptor depletion, suggesting that Deptor might not be the only target of EZH2 epigenetic regulation.

After inhibiting Deptor expression with siRNA, the effect of EZH2 inhibition-induced inactivation of mTOR complexes was reversed.

EZH2 bound the Deptor promoter region and then regulated its transcriptional level (Fig.  xref d).

A ChIP assay demonstrated that EZH2 bound the promoter region of Deptor, an endogenous inhibitor of mTORC1 and mTORC2, and regulated the transcription of Deptor by modulating H3K27me3 in its promoter region.

The binding of EZH2 to the Deptor promoter was determined by ChIP assay.

While this is the first report describing GzmB-mediated induction of neutrophil elastase activity to enhance hemidesmosomal protein loss in PDs, this does not exclude potential interactions between GzmB and other proteases in PDs.

Since recent studies combining genomics, proteomics, and bioinformatics are beginning to elucidate the direct and indirect mutual influence of proteases xref , our understanding of the complex interactions between GzmB and other proteases in PDs will be further refined.

Indeed, a recent work revealed that GzmB activates caspase 3 in secretory lysosomes of mast cells, a mechanism which possibly contributes to enhanced caspase 3-dependent proteolytic cleavage in the extracellular space xref .

This suggests that NTRK1 and the NGFR might not respond to AR signaling, and the roles of NGF–NGFR or NGF–NTRK1 signaling pathways might differ from that of NGF–CHRM4 signaling in prostate cancer.

This suggests that NTRK1 and the NGFR might not respond to AR signaling, and the roles of NGF–NGFR or NGF–NTRK1 signaling pathways might differ from that of NGF–CHRM4 signaling in prostate cancer.

They show that NGF interacts with the GPCR CHRM4, that both NGF and CHRM4 are upregulated in highly metastatic prostate cancer and that targeting NGF reduces therapy resistance in a mouse xenograft model.

The results suggest an approach for NEPC treatment by targeting NGF–CHRM4 signaling.

Since the activated PI3K/AKT pathway was reported to cross-talk with stimulated muscarinic receptor signaling xref , xref , and activated AKT is associated with MYCN expression in contributing to NEPC transformation xref , we hypothesized that stimulation of the NGF–CHRM4 axis might upregulate AKT-MYCN signaling in prostate cancer.

Since we showed that upregulated NGF cannot increase expression of CHRM1 and CHRM3 (Fig.  xref ; Supplementary Fig.  xref ), this result suggests that NGF–CHRM4 might be a unique signaling pathway involved in neuroendocrine differentiation of prostate cancer that differs from canonical acetylcholine–CHRM pathways.

NGF is associated with CHRM4 and was shown to be upregulated in high-grade and SCNC samples.

IHC analyses revealed that cytoplasmic NGF was associated with increased cytoplasmic CHRM4 and was highly expressed in high-grade tumors and SCNC samples (Fig.  xref ).

These results support that activation of NGF–CHRM4 signaling is connected to malignant progression and neuroendocrine differentiation of prostate cancer.

NGF physically interacts with CHRM4 after ADT.

To determine the possible interaction between NGF and CHRM4, AR-positive cells were subjected to ADT followed by an immunoprecipitation (IP)-Western blot analysis.

These observations confirm that the NGF physically interacts with CHRM4.

Our study demonstrated that inhibition of AR signaling decreases activation of the NGF–CHRM4 axis, which is associated with neuroendocrine differentiation of prostate cancer, suggesting that current hormonal therapy designed to suppress AR functions may predispose prostate cancer to NEPC development.

We demonstrated that the NGF physically interacts with CHRM4 and that the NGF mediates NEPC differentiation dependent on CHRM4.

This suggests that NTRK1 and the NGFR might not respond to AR signaling, and the roles of NGF–NGFR or NGF–NTRK1 signaling pathways might differ from that of NGF–CHRM4 signaling in prostate cancer.

The specificity of the NGF–CHRM4 interrelationship can be used to develop specific drugs that target this interaction.

Thus, our findings offer the potential to develop a prognostic information for current AR-directed therapeutic strategies with an antagonist of NGF–CHRM4 signaling.

Our study provides evidence that the NGF-CHRM4 axis has potential to be considered as a therapeutic target to impair NEPC progression.

A low LCR was identified in 21 patients and was significantly correlated with older age, a high CRP-albumin ratio, and advanced disease stage, and was a prognostic factor for OS and DFS.

The kinase activity of TAK1 leads to phosphorylation events that activate AP-1 and NF-κB. In parallel to cIAP-induced ubiquitination of RIPK2, XIAP’s enzymatic activity results in the formation of polyubiquitin chains on RIPK2, serving as a platform to engage another E3 ligase complex known as the Linear Ubiquitin Assembly Complex (LUBAC) ( xref , xref ).

K63-linked ubiquitination of RIPK2 has been established as a means to construct protein scaffolds that transduce downstream signaling.

In a step-wise fashion, ubiquitination of RIPK2 leads to activation and recruitment of the TAK1 complex, consisting of TAK1 in association with TAK1-binding protein (TAB)2 and 3.

Despite this focus, much of the nature of the NOD1 and 2 interaction with these structures remains unknown, although recent findings suggest that NOD2 directly binds MDP with high affinity ( xref ), with the N-glycosylated form specific to the mycobacterial cell wall triggering an exceptionally strong immunogenic response compared to N-acetyl MDP ( xref ).

Moreover, it was recently reported that bacterial acylated lipopeptides (acLP) activated NLRP7 and stimulated formation of an NLRP7-ASC-caspase-1 inflammasome ( xref ).

While this mechanism is still poorly understood, the ability of NLRP10 to interact with NOD1 as well as its signaling targets RIPK2, TAK1, and NEMO, suggests that NLRP10 may be involved in optimizing cytokine release following bacterial infections.

Few ligands have been found for NLRP1 to date, and include bacterial products such as lethal toxin (LT) produced by Bacillus anthracis which activates murine NLRP1b ( xref ), muramyl dipeptide (MDP), a component of bacterial peptidoglycan that activates human NLRP1; and reduced levels of cytosolic ATP ( xref – xref ).

Moreover, it was recently reported that bacterial acylated lipopeptides (acLP) activated NLRP7 and stimulated formation of an NLRP7-ASC-caspase-1 inflammasome ( xref ).

The data suggest that in hepatocytes merlin is functionally linked to the hippo pathway and acts upstream Mst1/2 by recruiting LATS to the membrane comparable to what has been shown in FH912 Schwann cell line.

Translocation of merlin to the nucleus allows merlin to bind and inhibit the E3 ubiquitin ligase CRL4 DCAF1 ( D DB1- and C ul4- A ssociated F actor 1) ( xref , xref ).

For example, in confluent human umbilical vein endothelial cells, merlin suppressed recruitment of Rac to the plasma membrane, and its silencing promoted recruitment of Rac1 to sites of extracellular matrix adhesion, and promoted cell growth ( xref ).

Previously, we showed that activation of ErbB2/ErbB3 receptors in primary rat Schwann cells by neuregulin-1 induced merlin phosphorylation at Ser518 via PKA ( xref ).

Merlin is phosphorylated at Ser10, Thr230 and Ser315 by Akt (also known as protein kinase B, PKB) and controls merlin’s proteasome-mediated degradation by ubiquitination to prevent its interaction with binding partners ( xref , xref ).

Merlin is phosphorylated at Ser10, Thr230 and Ser315 by Akt (also known as protein kinase B, PKB) and controls merlin’s proteasome-mediated degradation by ubiquitination to prevent its interaction with binding partners ( xref , xref ).

Merlin is phosphorylated at Ser10, Thr230 and Ser315 by Akt (also known as protein kinase B, PKB) and controls merlin’s proteasome-mediated degradation by ubiquitination to prevent its interaction with binding partners ( xref , xref ).

In sub-confluent primary Schwann cells, we found that merlin binds to paxillin and mediates merlin localization at the plasma membrane and association with β1-integrin and ErbB2, modifying the organization of the actin cytoskeleton in a cell density-dependent manner ( xref ).

Moreover, in cultured Schwann cells, merlin interaction with Amot was demonstrated by co-immunoprecipitation of the endogenous proteins ( xref ).

Merlin-Amot interaction was required for merlin regulation of mitogenic MAPK signaling.

Moreover, co-immunoprecipitation experiments revealed that merlin interacts with YAP1, although the interaction is not direct ( xref ).

Studies in human meningioma tumors and in paired cell lines—KY21MG1 or MENII-1 meningioma cell lines and AC1 arachnoidal cells—demonstrated that merlin loss was associated with increased YAP expression and nuclear localization.

Amot-p130 isoform bound to the WW domains of YAP and blocked LATS1 access to YAP.

The activation of Rac1 through CD44 was identified via the interaction of CD44 with Tiam-1, a Rac1 guanine nucleotide exchange factor (GEF) that catalyzes the replacement of the tightly-bound GDP with GTP.

Merlin inactivation of Src signaling was also shown in CNS glial cells, where merlin competitively inhibits Src binding to ErbB2 thereby preventing ErbB2-mediated Src phosphorylation and downstream mitogenic signaling.

Merlin interacts with tubulin and acetylated-tubulin and stabilizes the microtubules by attenuating tubulin turnover—lowering the rates of microtubule polymerization and depolymerization.

HDAC inhibitors disrupt the PP1-HDAC interaction facilitating Akt dephosphorylation and decrease human meningioma and schwannoma cell proliferation and schwannoma growth in an allograft model and meningioma growth in an intracranial xenograft model ( xref , xref , xref ).

Hyaluronan-CD44 interaction in astrocytes and an immortalized mouse mammary epithelial cell line, EpH4, leads to Rac1 signaling activation and actin cytoskeleton rearrangement ( xref , xref ).

Finally, a recent meningioma study of 73 patients found a high incidence of TERT promoter activating mutations in meningiomas undergoing malignant transformation in both NF2-related and sporadic meningiomas, whereas no TERT mutations were found in benign tumors.

The data suggest that in hepatocytes merlin is functionally linked to the hippo pathway and acts upstream Mst1/2 by recruiting LATS to the membrane comparable to what has been shown in FH912 Schwann cell line.

Translocation of merlin to the nucleus allows merlin to bind and inhibit the E3 ubiquitin ligase CRL4 DCAF1 ( D DB1- and C ul4- A ssociated F actor 1) ( xref , xref ).

For example, in confluent human umbilical vein endothelial cells, merlin suppressed recruitment of Rac to the plasma membrane, and its silencing promoted recruitment of Rac1 to sites of extracellular matrix adhesion, and promoted cell growth ( xref ).

Previously, we showed that activation of ErbB2/ErbB3 receptors in primary rat Schwann cells by neuregulin-1 induced merlin phosphorylation at Ser518 via PKA ( xref ).

Merlin is phosphorylated at Ser10, Thr230 and Ser315 by Akt (also known as protein kinase B, PKB) and controls merlin’s proteasome-mediated degradation by ubiquitination to prevent its interaction with binding partners ( xref , xref ).

Merlin is phosphorylated at Ser10, Thr230 and Ser315 by Akt (also known as protein kinase B, PKB) and controls merlin’s proteasome-mediated degradation by ubiquitination to prevent its interaction with binding partners ( xref , xref ).

Merlin is phosphorylated at Ser10, Thr230 and Ser315 by Akt (also known as protein kinase B, PKB) and controls merlin’s proteasome-mediated degradation by ubiquitination to prevent its interaction with binding partners ( xref , xref ).

In sub-confluent primary Schwann cells, we found that merlin binds to paxillin and mediates merlin localization at the plasma membrane and association with β1-integrin and ErbB2, modifying the organization of the actin cytoskeleton in a cell density-dependent manner ( xref ).

Moreover, in cultured Schwann cells, merlin interaction with Amot was demonstrated by co-immunoprecipitation of the endogenous proteins ( xref ).

Merlin-Amot interaction was required for merlin regulation of mitogenic MAPK signaling.

Moreover, co-immunoprecipitation experiments revealed that merlin interacts with YAP1, although the interaction is not direct ( xref ).

Studies in human meningioma tumors and in paired cell lines—KY21MG1 or MENII-1 meningioma cell lines and AC1 arachnoidal cells—demonstrated that merlin loss was associated with increased YAP expression and nuclear localization.

Amot-p130 isoform bound to the WW domains of YAP and blocked LATS1 access to YAP.

The activation of Rac1 through CD44 was identified via the interaction of CD44 with Tiam-1, a Rac1 guanine nucleotide exchange factor (GEF) that catalyzes the replacement of the tightly-bound GDP with GTP.

Merlin inactivation of Src signaling was also shown in CNS glial cells, where merlin competitively inhibits Src binding to ErbB2 thereby preventing ErbB2-mediated Src phosphorylation and downstream mitogenic signaling.

Merlin interacts with tubulin and acetylated-tubulin and stabilizes the microtubules by attenuating tubulin turnover—lowering the rates of microtubule polymerization and depolymerization.

HDAC inhibitors disrupt the PP1-HDAC interaction facilitating Akt dephosphorylation and decrease human meningioma and schwannoma cell proliferation and schwannoma growth in an allograft model and meningioma growth in an intracranial xenograft model ( xref , xref , xref ).

Hyaluronan-CD44 interaction in astrocytes and an immortalized mouse mammary epithelial cell line, EpH4, leads to Rac1 signaling activation and actin cytoskeleton rearrangement ( xref , xref ).

Finally, a recent meningioma study of 73 patients found a high incidence of TERT promoter activating mutations in meningiomas undergoing malignant transformation in both NF2-related and sporadic meningiomas, whereas no TERT mutations were found in benign tumors.

The data suggest that in hepatocytes merlin is functionally linked to the hippo pathway and acts upstream Mst1/2 by recruiting LATS to the membrane comparable to what has been shown in FH912 Schwann cell line.

Translocation of merlin to the nucleus allows merlin to bind and inhibit the E3 ubiquitin ligase CRL4 DCAF1 ( D DB1- and C ul4- A ssociated F actor 1) ( xref , xref ).

For example, in confluent human umbilical vein endothelial cells, merlin suppressed recruitment of Rac to the plasma membrane, and its silencing promoted recruitment of Rac1 to sites of extracellular matrix adhesion, and promoted cell growth ( xref ).

Previously, we showed that activation of ErbB2/ErbB3 receptors in primary rat Schwann cells by neuregulin-1 induced merlin phosphorylation at Ser518 via PKA ( xref ).

Merlin is phosphorylated at Ser10, Thr230 and Ser315 by Akt (also known as protein kinase B, PKB) and controls merlin’s proteasome-mediated degradation by ubiquitination to prevent its interaction with binding partners ( xref , xref ).

Merlin is phosphorylated at Ser10, Thr230 and Ser315 by Akt (also known as protein kinase B, PKB) and controls merlin’s proteasome-mediated degradation by ubiquitination to prevent its interaction with binding partners ( xref , xref ).

Merlin is phosphorylated at Ser10, Thr230 and Ser315 by Akt (also known as protein kinase B, PKB) and controls merlin’s proteasome-mediated degradation by ubiquitination to prevent its interaction with binding partners ( xref , xref ).

In sub-confluent primary Schwann cells, we found that merlin binds to paxillin and mediates merlin localization at the plasma membrane and association with β1-integrin and ErbB2, modifying the organization of the actin cytoskeleton in a cell density-dependent manner ( xref ).

Moreover, in cultured Schwann cells, merlin interaction with Amot was demonstrated by co-immunoprecipitation of the endogenous proteins ( xref ).

Merlin-Amot interaction was required for merlin regulation of mitogenic MAPK signaling.

Moreover, co-immunoprecipitation experiments revealed that merlin interacts with YAP1, although the interaction is not direct ( xref ).

Studies in human meningioma tumors and in paired cell lines—KY21MG1 or MENII-1 meningioma cell lines and AC1 arachnoidal cells—demonstrated that merlin loss was associated with increased YAP expression and nuclear localization.

Amot-p130 isoform bound to the WW domains of YAP and blocked LATS1 access to YAP.

The activation of Rac1 through CD44 was identified via the interaction of CD44 with Tiam-1, a Rac1 guanine nucleotide exchange factor (GEF) that catalyzes the replacement of the tightly-bound GDP with GTP.

Merlin inactivation of Src signaling was also shown in CNS glial cells, where merlin competitively inhibits Src binding to ErbB2 thereby preventing ErbB2-mediated Src phosphorylation and downstream mitogenic signaling.

Merlin interacts with tubulin and acetylated-tubulin and stabilizes the microtubules by attenuating tubulin turnover—lowering the rates of microtubule polymerization and depolymerization.

HDAC inhibitors disrupt the PP1-HDAC interaction facilitating Akt dephosphorylation and decrease human meningioma and schwannoma cell proliferation and schwannoma growth in an allograft model and meningioma growth in an intracranial xenograft model ( xref , xref , xref ).

Hyaluronan-CD44 interaction in astrocytes and an immortalized mouse mammary epithelial cell line, EpH4, leads to Rac1 signaling activation and actin cytoskeleton rearrangement ( xref , xref ).

Finally, a recent meningioma study of 73 patients found a high incidence of TERT promoter activating mutations in meningiomas undergoing malignant transformation in both NF2-related and sporadic meningiomas, whereas no TERT mutations were found in benign tumors.

Taken together, our findings suggest that the inhibitory effect of PTEN on BMP9-induced osteogenic differentiation may be mediated through reducing the expression of Wnt10b, and PTEN may inhibit Wnt10b by partly disturbing the interaction between CREB and BMP/Smad signaling.

We find that PTEN is inhibited by BMP9 in MSCs, but Wnt10b is increased simultaneously.

Because BMP9 inhibited PTEN and increased Wnt10b simultaneously, Wnt10b may be implicated in the suppressive effects of PTEN on the osteogenic potential of BMP9.

In our previous studies, we find that PTEN is inhibited by BMP9, but Wnt10b is increased concurrently (Huang et al., xref ; Liao et al., xref ).

In this study, we confirmed that BMP9 inhibits PTEN and increases Wnt10b simultaneously in MSCs.

Taken together, our findings suggest that the inhibitory effect of PTEN on BMP9-induced osteogenic differentiation may be mediated through reducing the expression of Wnt10b, and PTEN may inhibit Wnt10b by partly disturbing the interaction between CREB and BMP/Smad signaling.

We find that PTEN is inhibited by BMP9 in MSCs, but Wnt10b is increased simultaneously.

Because BMP9 inhibited PTEN and increased Wnt10b simultaneously, Wnt10b may be implicated in the suppressive effects of PTEN on the osteogenic potential of BMP9.

In our previous studies, we find that PTEN is inhibited by BMP9, but Wnt10b is increased concurrently (Huang et al., xref ; Liao et al., xref ).

In this study, we confirmed that BMP9 inhibits PTEN and increases Wnt10b simultaneously in MSCs.

Chronic S15 phosphorylation of mutant p53 has been found in tumors where DNA damage signaling is constitutively activated ( xref , xref ).

Further, NF-kB inhibition by overexpression of IkB also results in S15 phosphorylation of mutant p53 via GADD45α mediated JNK1 activation ( xref ).

It may form a complex with mutant p53 and MDM2 to block their ubiquitination mediated degradation or may form a complex with mutant p53 to prevent aggregation of mutant p53 by inhibiting MDM2 and CHIP in multiple cancer cell lines ( xref , xref ).

A recent study by Capaci et al. showed that mutant p53 can interact with HIF1α to induce miR-30d expression which promotes tubulo-vesiculation of Golgi apparatus leading to enhanced vesicular trafficking and secretion ( xref ) ( xref ).

Binding of mutant p53 to ETS2 can promote expression of Pla2g16 or nucleotide synthesis genes required for invasion depending upon the cancer type ( xref ) ( xref , xref ).

Furthermore, the binding of mutant p53 to EGR1 promotes MYO10 expression which drives breast cancer cell invasion ( xref ) ( xref ).

Further, mutant p53 can interact with PELP1 to promote resistance to platinum-based drugs in triple negative breast cancer ( xref ).

A further study reported that mutant p53 enhance the association of mutant p53 and PARP on the replicating DNA ( xref ) ( xref ).

GOF mutant p53 can bind to TopBP1 and attenuate ATR checkpoint response during replication stress ( xref ) ( xref ).

The compound, RETRA disrupts mutant p53-p73 complex restoring p73-dependent transcription and apoptosis ( xref ) ( xref ).

Short Interfering Mutant p53 Peptides (SIMP) can interact with different mutant p53 proteins and release p73, while peptides aptamers (PA) can inhibit mutant p53 transcription ( xref ) ( xref ).

Zhou et al. showed that mutant p53 binds to novel interacting partner AMPKα in glucose starvation conditions and inhibits its activation by other kinases leading to increased aerobic glycolysis, lipid production, and cell growth ( xref ) ( xref ).

This eliminates mitochondria-associated p53 which would otherwise be activated by PINK1 to mediate suppression of Nanog ( xref ) ( xref ).

Acetylation of p53 at K373 by CBP/p300 leads to dissociation of HDM2 and TRIM24 and subsequent activation of p53 which in turn transcriptionally activates p21, miR-34a, and miR-145 ( xref ).

A recent study by Alam et al. reveals GOF mutant p53 upregulates EFNB2 and activates ephrin B2 reverse signaling to impart enhanced chemoresistance to colorectal cancer cells ( xref ) ( xref ).

Acetylation of p53 at K373 by CBP/p300 leads to dissociation of HDM2 and TRIM24 and subsequent activation of p53 which in turn transcriptionally activates p21, miR-34a, and miR-145 ( xref ).

Chronic S15 phosphorylation of mutant p53 has been found in tumors where DNA damage signaling is constitutively activated ( xref , xref ).

Further, NF-kB inhibition by overexpression of IkB also results in S15 phosphorylation of mutant p53 via GADD45α mediated JNK1 activation ( xref ).

It may form a complex with mutant p53 and MDM2 to block their ubiquitination mediated degradation or may form a complex with mutant p53 to prevent aggregation of mutant p53 by inhibiting MDM2 and CHIP in multiple cancer cell lines ( xref , xref ).

A recent study by Capaci et al. showed that mutant p53 can interact with HIF1α to induce miR-30d expression which promotes tubulo-vesiculation of Golgi apparatus leading to enhanced vesicular trafficking and secretion ( xref ) ( xref ).

Binding of mutant p53 to ETS2 can promote expression of Pla2g16 or nucleotide synthesis genes required for invasion depending upon the cancer type ( xref ) ( xref , xref ).

Furthermore, the binding of mutant p53 to EGR1 promotes MYO10 expression which drives breast cancer cell invasion ( xref ) ( xref ).

Further, mutant p53 can interact with PELP1 to promote resistance to platinum-based drugs in triple negative breast cancer ( xref ).

A further study reported that mutant p53 enhance the association of mutant p53 and PARP on the replicating DNA ( xref ) ( xref ).

GOF mutant p53 can bind to TopBP1 and attenuate ATR checkpoint response during replication stress ( xref ) ( xref ).

The compound, RETRA disrupts mutant p53-p73 complex restoring p73-dependent transcription and apoptosis ( xref ) ( xref ).

Short Interfering Mutant p53 Peptides (SIMP) can interact with different mutant p53 proteins and release p73, while peptides aptamers (PA) can inhibit mutant p53 transcription ( xref ) ( xref ).

Zhou et al. showed that mutant p53 binds to novel interacting partner AMPKα in glucose starvation conditions and inhibits its activation by other kinases leading to increased aerobic glycolysis, lipid production, and cell growth ( xref ) ( xref ).

This eliminates mitochondria-associated p53 which would otherwise be activated by PINK1 to mediate suppression of Nanog ( xref ) ( xref ).

Acetylation of p53 at K373 by CBP/p300 leads to dissociation of HDM2 and TRIM24 and subsequent activation of p53 which in turn transcriptionally activates p21, miR-34a, and miR-145 ( xref ).

A recent study by Alam et al. reveals GOF mutant p53 upregulates EFNB2 and activates ephrin B2 reverse signaling to impart enhanced chemoresistance to colorectal cancer cells ( xref ) ( xref ).

Acetylation of p53 at K373 by CBP/p300 leads to dissociation of HDM2 and TRIM24 and subsequent activation of p53 which in turn transcriptionally activates p21, miR-34a, and miR-145 ( xref ).

Functionally, our findings confirmed that inhibition of PTEN by PTEN siRNA or specific inhibitor not only ameliorated secondary hippocampal injury but also promoted hippocampal-dependent cognition and memory recovery, suggesting important neuroprotective effects against hemorrhagic insults.

Functionally, our findings confirmed that inhibition of PTEN by PTEN siRNA or specific inhibitor not only ameliorated secondary hippocampal injury but also promoted hippocampal-dependent cognition and memory recovery, suggesting important neuroprotective effects against hemorrhagic insults.

PTEN is induced by P53 in the early and late stages of cell response, and PTEN and P53 interact ( xref , xref ).

Moreover, P53 regulates PTEN in the early and late stages of cell response, and there PTEN and P53 interact ( xref , xref ).

Activated STAT3 can bind to the P53 promoter, then inhibit P53 expression in a STAT3-dependent manner ( xref , xref ).

Runx2 is a master transcription factor involved in bone formation and vascular calcification, and P53 can interact with Runx2 during osteogenic differentiation ( xref ).

PTEN is induced by P53 in the early and late stages of cell response, and PTEN and P53 interact ( xref , xref ).

Moreover, P53 regulates PTEN in the early and late stages of cell response, and there PTEN and P53 interact ( xref , xref ).

Activated STAT3 can bind to the P53 promoter, then inhibit P53 expression in a STAT3-dependent manner ( xref , xref ).

Runx2 is a master transcription factor involved in bone formation and vascular calcification, and P53 can interact with Runx2 during osteogenic differentiation ( xref ).

A comparable example of this possibility is the activation of the cyclin-dependent kinase inhibitor p21 by p53.

A comparable example of this possibility is the activation of the cyclin-dependent kinase inhibitor p21 by p53.

The precise mechanism of how LASP1 promotes PTEN ubiquitination still remains elusive xref .

In another study, the heat shock-like protein Clusterin was shown to increase AKT2 activity and promote the motility of both normal and malignant prostate cells via an inhibitory activity on PTEN-S380 phosphorylation and consequent inactivation of PTEN xref .

Another study demonstrated that phosphorylation of PTEN on tyrosine 240 by FGFR2 promotes chromatin binding through an interaction with Ki-67, which facilitates the recruitment of RAD51 to promote DNA repair xref . xref summarises these novel functions and signalling axes of nuclear PTEN.

It was reported that PTEN could dephosphorylate PGK1, a glycolytic enzyme and protein kinase with a tumorigenic role in glioblastoma xref .

Dephosphorylation of PGK1 by PTEN was found to inhibit its activity, downstream glycolytic functions, and glioblastoma cell proliferation xref , thereby presenting another mechanism in which PTEN functions as a tumour suppressor.

The precise mechanism of how LASP1 promotes PTEN ubiquitination still remains elusive xref .

In another study, the heat shock-like protein Clusterin was shown to increase AKT2 activity and promote the motility of both normal and malignant prostate cells via an inhibitory activity on PTEN-S380 phosphorylation and consequent inactivation of PTEN xref .

Another study demonstrated that phosphorylation of PTEN on tyrosine 240 by FGFR2 promotes chromatin binding through an interaction with Ki-67, which facilitates the recruitment of RAD51 to promote DNA repair xref . xref summarises these novel functions and signalling axes of nuclear PTEN.

It was reported that PTEN could dephosphorylate PGK1, a glycolytic enzyme and protein kinase with a tumorigenic role in glioblastoma xref .

Dephosphorylation of PGK1 by PTEN was found to inhibit its activity, downstream glycolytic functions, and glioblastoma cell proliferation xref , thereby presenting another mechanism in which PTEN functions as a tumour suppressor.

Furthermore, IR induced RAC1 expression and activity via the activation of PI3K/AKT signaling pathway, and then enhancing cell proliferation, survival, migration and metastasis and increasing levels of epithelial-to-mesenchymal transition (EMT) markers, which facilitated the cell survival and invasive phenotypes.

As exhibited in xref , RAC1 overexpression led to the up-regulation of GST-RAC1, RAC1, PAK1, p-PAK1, LIMK1, p-LIMK1, Cofilin, and p-Cofilin in A549 and PC9 cells, while the opposite pattern of these genes was found in the A549 and PC9 cells after Rac1 knockdown.

E.g., RAC1 is activated by IR and the inhibition of RAC1 abrogates G2 checkpoint activation and cell survival following IR in breast cancer cells ( xref , xref ).

Interestingly, CRP-induced MMP9 expression and invasion on RA-FLSs were p38-dependent as addition of a p38 inhibitor (SB202190) but not a NF-κB inhibitor (PDTC) was capable of inhibiting CRP-induced MMP9 expression and cell invasion.

In contrast, blockade of CD16 produced no inhibitory effect on CRP-induced expression of CXCL8, CCL2, MMP9 and IL-6 by RA-FLSs ( xref ), suggesting that CRP may not signal through the CD16 to induce joint inflammation in vitro .

In contrast, blockade of CD16 produced no inhibitory effect on CRP-induced expression of CXCL8, CCL2, MMP9 and IL-6 by RA-FLSs ( xref ), suggesting that CRP may not signal through the CD16 to induce joint inflammation in vitro .

However, CRP- induced expression of CXCL8 was CD32-dependent as it was blunted by the antibody against CD32, whereas CRP-induced MMP9 was blocked by the antibody to CD64, demonstrating that differential signaling mechanisms for CRP in regulating CXCL8 and MMP9 expression in RA-FLSs.

In contrast, blockade of CD16 produced no inhibitory effect on CRP-induced expression of CXCL8, CCL2, MMP9 and IL-6 by RA-FLSs ( xref ), suggesting that CRP may not signal through the CD16 to induce joint inflammation in vitro .

As shown in xref , CRP-induced expression of CCL2 and IL-6 was blocked by either neutralizing antibody to CD32 or CD64 or both, suggesting that CRP signals through both CD32/CD64 to induce expression of CCL2 and IL-6.

In contrast, blockade of CD16 produced no inhibitory effect on CRP-induced expression of CXCL8, CCL2, MMP9 and IL-6 by RA-FLSs ( xref ), suggesting that CRP may not signal through the CD16 to induce joint inflammation in vitro .

As shown in xref , CRP-induced expression of CCL2 and IL-6 was blocked by either neutralizing antibody to CD32 or CD64 or both, suggesting that CRP signals through both CD32/CD64 to induce expression of CCL2 and IL-6.

It has been reported that CRP-induced cytokine expression is also regulated by TWIST transcriptionally in myeloma cells ( xref ).

We thus blocked CD32 or CD64 or both with neutralizing antibodies to differentially determine the signaling mechanisms of CRP-induced cytokine expression.

Also, the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular-signal-regulated kinase (ERK) were stimulated by S100A8, which had an analogous effect to the lipopolysaccharide (LPS) treatment ( xref C–E).

Also, the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular-signal-regulated kinase (ERK) were stimulated by S100A8, which had an analogous effect to the lipopolysaccharide (LPS) treatment ( xref C–E).