In various cell types, the binding of hyaluronan to CD44 stimulates Tiam1 dependent Rac1 signaling and cytoskeleton mediated tumor cell migration.

In various cell types, the binding of hyaluronan to CD44 stimulates Tiam1 dependent Rac1 signaling and cytoskeleton mediated tumor cell migration.

First, protein kinase C potentiated phosphatase inhibitor (CPI-17), which is frequently overexpressed in mesothelioma tumors, inhibits merlin phosphatase MYPT1-PP1delta, providing one potential pathway by which merlin 's tumor suppressor function might be inactivated through maintenance of phosphorylation at Ser518.

First, protein kinase C potentiated phosphatase inhibitor (CPI-17), which is frequently overexpressed in mesothelioma tumors, inhibits merlin phosphatase MYPT1-PP1delta, providing one potential pathway by which merlin 's tumor suppressor function might be inactivated through maintenance of phosphorylation at Ser518.

In various cell types, the binding of hyaluronan to CD44 stimulates Tiam1 dependent Rac1 signaling and cytoskeleton mediated tumor cell migration.

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.

We recently showed that PI3K inhibition in merlin deficient mouse Schwann cells selectively decreased their proliferation.

In primary rat Schwann cells, CD44 was shown to constitutively associate with the heterodimer receptor tyrosine kinase ErbB2 and ErbB3 and CD44 enhanced neuregulin induced ErbB2 activating phosphorylation.

Moreover, neuregulin survival signaling through the ErbB2 and ErbB3 receptor activates PI3K in rat Schwann cells through the activation of Akt and inhibition of Bad, a pro apoptotic Blc-2 family protein.

In the canonical hippo pathway, mammalian Ste20 like kinases (Mst1/2; hippo homolog) phosphorylate large tumor suppressor kinases (LATS 1/2), which in turn phosphorylate and inactivate YAP and TAZ, blocking their role as TEAD and MEAD transcription factor co-activators.

SOS is a GEF that activates Ras by catalyzing the nucleotide exchange.

The BMP9 induced phosphorylation of CREB or Smad1/5/9 is also reduced by PTEN, but enhanced by PTEN knockdown.

The BMP9 induced phosphorylation of CREB or Smad1/5/9 is also reduced by PTEN, but enhanced by PTEN knockdown.

PTEN Reduces BMP9 Induced Osteogenic Differentiation Through Inhibiting Wnt10b in Mesenchymal Stem Cells.

On the contrary, knockdown of PTEN potentiated the effects of BMP9 on Runx2 (XREF_FIG), OPN (XREF_FIG), and mineralization (XREF_FIG).

H&E staining results also show that knockdown of PTEN potentiated the effect of BMP9 on increasing trabecular bone, and knockdown of Wnt10b exhibited a reversal effect and almost diminished the effect of PTEN knockdown on enhancing BMP9 induced bone formation (XREF_FIG).

Thus, we speculate that PTEN may reduce the potential of BMP9 on activating Wnt and beta-catenin through inhibiting the expression of Wnt10b in multiple progenitor cells.

As reported, PTEN can reduce the activation of the Wnt and beta-catenin signaling pathway through regulating the phosphorylation of GSK3beta.

PTEN Reduces BMP9-Induced Osteogenic Differentiation Through Inhibiting Wnt10b in Mesenchymal Stem Cells.

The BMP9 increased Wnt10b is decreased by PTEN but enhanced by knockdown of PTEN.

Hence, Wnt10b may be negatively regulated by PTEN through PI3K/Akt/mTOR signaling.

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.

In this study , we demonstrate that the inhibitory effect of PTEN on BMP9-induced osteogenic differentiation can be partially reversed by Wnt10b , and the expression of Wnt10b can be inhibited by PTEN through disturbing the interaction between CREB and BMP / Smad signaling at least .

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

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.

Our previous study shows that PTEN is downregulated by BMP9 during the osteogenic process in MSCs.

In our previous studies, we find that PTEN is inhibited by BMP9, but Wnt10b is increased concurrently.

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

Our previous study shows that PTEN is downregulated by BMP9 during the osteogenic process in MSCs ( Huang et al ., 2014 ) .

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

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.

However, knockdown of Wnt10b almost abolished the effect of PTEN knockdown on promoting BMP9 induced bone formation (XREF_FIG).

H&E staining results also show that knockdown of PTEN potentiated the effect of BMP9 on increasing trabecular bone, and knockdown of Wnt10b exhibited a reversal effect and almost diminished the effect of PTEN knockdown on enhancing BMP9 induced bone formation (XREF_FIG).

In this study, we determined whether PTEN could reduce the expression of Wnt10b during the osteogenic process initialized by BMP9 in mesenchymal stem cells (MSCs) and the possible molecular mechanism.

These data suggest that PTEN may negatively regulate the expression of Wnt10b in MSCs at least.

In this study, we demonstrate that the inhibitory effect of PTEN on BMP9 induced osteogenic differentiation can be partially reversed by Wnt10b, and the expression of Wnt10b can be inhibited by PTEN through disturbing the interaction between CREB and BMP and Smad signaling at least.

Meanwhile, PTEN may modulate the activity of Wnt and beta-catenin signaling via a Wnt10b dependent manner although the concrete process needs to be further unveiled.

However, it remains unknown whether PTEN could modulate the activation of Wnt and beta-catenin signaling through regulating the expression of Wnt10b.

Meanwhile, PTEN may modulate the activity of Wnt and beta-catenin signaling via a Wnt10b dependent manner although the concrete process needs to be further unveiled.

However, it remains unknown whether PTEN could modulate the activation of Wnt and beta-catenin signaling through regulating the expression of Wnt10b.

Although Wnt10b may reverse the suppressive effect of PTEN on the osteogenic potential of BMP9, the concrete relationship between them is unclear.

In this study, we determined whether Wnt10b could reverse the inhibitory effect of PTEN on the BMP9 induced osteogenic process in MSCs and dissect the possible relationship between PTEN and Wnt10b during the osteoblastic commitment initialized by BMP9 in progenitor cells.

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 ).

On the contrary , Nanog suppresses p53 activity while Gli activated by Nanog inhibits p53 by activating Mdm2 to promote pluripotency .

p53 loss upregulates CD133 which subsequently promotes CSC marker expression and confers stemness .

For example , p53 repress CD133 by directly binding to its promoter and recruiting HDAC1 ( Figure 2 ) .

With the advent of reprogramming era , it was further highlighted that p53 loss promote dedifferentiation and reprogramming under favorable conditions .

Loss or gain-of-function mutations in TP53 induce dedifferentiation and proliferation of SCs with damaged DNA leading to the generation of CSCs.

TP53 maintains homeostasis between self-renewal and differentiation depending on the cellular and developmental state and prevents the dedifferentiation and reprogramming of somatic cells to stem cells.

With the advent of reprogramming era, it was further highlighted that p53 loss promote dedifferentiation and reprogramming under favorable conditions.

Furthermore, p53 loss was found to trigger dedifferentiation of mature hepatocytes to pluripotent cells by the activation of SC marker Nestin, which remains suppressed in wild-type p53 bearing cells (XREF_FIG).

While wild type p53 suppresses inflammatory response by inhibiting the production of cytokines and antagonizing NF-kB activity, mutant p53 on the other hand enhances NF-kB activity in response to TNF-alpha and promotes inflammation (XREF_FIG).

Mutant p53 can itself disrupt the balance between stem cell proliferation and differentiation as well as sequester p63 or p73 thereby hindering apoptosis, augmenting proliferation, and driving chemoresistance and metastasis typical of cancer stem cells.

Mutant p53 mediated repression of p63 function can also modulate the expression of certain miRNAs involved in invasion and metastasis such as let-7i, miR-155, miR-205, miR-130b, and miR-27a (XREF_FIG).

Hence, loss of NUMB in breast cancer cells leads to decreased p53 levels and increased activity of NOTCH receptor which confers increased chemoresistance.

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 ).

Mutant p53 and p63 complex can increase RAB coupling protein (RCP)-mediated recycling of cell surface growth promoting receptors.

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_FIG).

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

Further, the human p53 isoform Delta133p53beta lacking the transactivation domain was observed to promote CSC features in breast cancer cell lines by expression of Sox2, Oct3/4, and Nanog in a Delta133p53beta dependent manner.

Acetylation of p53 at K373 by CBP and 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_FIG).

Further , induction of miR-34a by p53 functionally targets the CSC marker CD44 , thereby inhibiting prostate cancer regeneration and metastasis ( Figure 2 ) ( 74 ) .

Additionally , p53 upregulates miR-34a that represses Notch ( Figure 2 ) and anti-apoptotic Bcl2 thereby promoting differentiation and apoptosis ( 82 ) .

Acetylation of p53 at K373 by CBP and 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_FIG).

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 ).

Inactivation of p53 disrupts this balance and promotes pluripotency and somatic cell reprogramming .

Inactivation of p53 disrupts this balance and promotes pluripotency and somatic cell reprogramming .

Mutant p53 implicate various context and tissue dependent mechanisms to promote cancer cell invasion and metastasis.

Various transcription factors such as NF-Y, SREBPs, ETS, and EGFR1 play crucial role in mutant p53 driven invasion and metastasis.

Mutant p53 implicate various context and tissue dependent mechanisms to promote cancer cell invasion and metastasis.

Various transcription factors such as NF-Y, SREBPs, ETS, and EGFR1 play crucial role in mutant p53 driven invasion and metastasis.

This suggests that acetylation at K320 and K373 can alter the structure of mutant p53 and restore wild type p53 functions.

Mutant p53 can also induce YAP and TAZ nuclear localization by interacting with SREBP and activating the mevalonate pathway.

Mutant p53 can also promote proliferation by inducing the REG-gamma proteosome pathway in association with p300 (XREF_FIG).

GOF mutant p53 can modify the tumor microenvironment and has been found to support chronic inflammation.

While wild type p53 suppresses inflammatory response by inhibiting the production of cytokines and antagonizing NF-kB activity, mutant p53 on the other hand enhances NF-kB activity in response to TNF-alpha and promotes inflammation (XREF_FIG).

In absence of AMPK, mitochondrial stress augments aerobic glycolysis, also called " Warburg effect " in tumor cells, which is promoted by mutant p53.

Several evidence demonstrate that mutant p53 promotes glycolysis and reprograms the cellular metabolism of cancer cells.

Gain-of function mutant p53 further promotes EMT and stemness phenotypes by activating genes regulating them.

Although these studies highlight that mutant p53 mediated EMT phenotype confer stemness in cancer cells, however, there is still a lot to explore in context of molecular mechanisms of mutant p53 driven stemness through activation of EMT genes.

However, whether mutant p53 induced EMT trigger stemness properties in cancer cells, is still quite unexplored.

While wild type p53 suppresses inflammatory response by inhibiting the production of cytokines and antagonizing NF-kB activity, mutant p53 on the other hand enhances NF-kB activity in response to TNF-alpha and promotes inflammation (XREF_FIG).

The sustained activation of NF-kB signaling by mutant p53 not only elevate inflammatory response but also protects the cancer cells from cytotoxic effects of tumor microenvironment by activating pro survival pathways.

Interaction of mutant p53 to SREBPs activates mevalonate pathway that promotes invasion in breast cancer cells (XREF_FIG).

Mutant p53 can also induce YAP and TAZ nuclear localization by interacting with SREBP and activating the mevalonate pathway.

Similarly, p53 activation by nutlin leads to transcriptional activation of p21 that cause cell cycle arrest and induces differentiation in human ESCs.

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 ).

To examine whether FoxO3a is required for PTEN mediated negative regulation of autophagy, we analyzed the mRNA levels of ATG5, ATG7, and ATG12 in the ipsilateral hippocampus post-ICH.

In the present study, PTEN inhibition not only reduced the levels of autophagy related proteins but also activated the PI3K and AKT pathway in the ipsilateral hippocampus after ICH.

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.

Specifically, PTEN antagonized the PI3K and AKT signaling and downstream effector FoxO3a phosphorylation and subsequently enhanced nuclear translocation of FoxO3a to drive proautophagy gene program, but these changes were diminished upon PTEN inhibition.

Mechanistically, blockage of PTEN could enhance FoxO3a phosphorylation modification to restrict its nuclear translocation and ATG transcription via activating the PI3K and AKT pathway, leading to the suppression of the autophagic program.

Inhibition of PTEN Ameliorates Secondary Hippocampal Injury and Cognitive Deficits after Intracerebral Hemorrhage : Involvement of AKT / FoxO3a / ATG-Mediated Autophagy .

Inhibition of PTEN Ameliorates Secondary Hippocampal Injury and Cognitive Deficits after Intracerebral Hemorrhage : Involvement of AKT / FoxO3a / ATG-Mediated Autophagy Spontaneous intracerebral hemorrhage ( ICH ) commonly causes secondary hippocampal damage and delayed cognitive impairments , but the mechanisms remain elusive .

According to these data, we speculate that posthemorrhagic PTEN elevation triggers the nuclear accumulation of FoxO3a and subsequent transcriptional activation of ATGs, resulting in sequential activation of autophagy.

Herein, we identified that ICH induced a significant increase in ATG transcriptional levels including ATG5, ATG7, and ATG12, which was strongly associated with PTEN mediated FoxO3a nuclear translocation.

PTEN Inhibition Reverses Secondary Hippocampal Injury Post-ICH.

Also, inactivation of the PI3K/AKT/mTOR pathway has been implicated in PTEN induced autophagy initiation [XREF_BIBR, XREF_BIBR].

However , blockage of PTEN prominently abolished these ATG transcriptions and subsequent autophagy induction .

These findings demonstrated that PLG reduces the calcification in VSMCs by regulating P53, indicating that P53 plays an important role in the calcification of VSMCs.

These experiments demonstrate that PLG attenuates arterial calcification by upregulating the P53 and PTEN signaling pathway and that this inhibitory effect on calcification can be blocked by P53 knockdown.

In various types of cancer cells, PLG significantly enhances the expression of wild-type P53 and PUMA, and it inhibits the expression of many pro survival proteins, such as BCL2, survivin and XIAP.

PLG has antitumour activity and significantly increases the expression of wild-type P53.

Similarly, the expression of P53 in the Vit D group was significantly reduced, and PLG treatment effectively increased the expression of P53 in the aorta (XREF_FIG).

These results showed that PLG upregulated the expression of P53 during vascular calcification by reducing STAT3 phosphorylation.

Western blotting and qRT-PCR analyses showed that high calcium and phosphate treatment reduced the P53 expression level in VSMCs and that PLG significantly increased the P53 expression level compared to the control group.

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 ).

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

In the case of high calcium / phosphate treatment , the expression of P53 was decreased , while PLG increased the expression of PTEN .

PLG promotes PTEN expression by increasing P53 signaling .

The effective PLG concentration used (10 to 15 muM) to induce apoptosis in tumor cells increases P53 by three- to four-fold compared to the level in control cells.

We hypothesize that P53 activation by PLG in VSMCs is mediated by decreased activation of STAT3.

Western blotting and qRT-PCR analyses showed that high calcium / phosphate treatment reduced the P53 expression level in VSMCs and that PLG significantly increased the P53 expression level compared to the control group .

These results showed that PLG upregulated the expression of P53 during vascular calcification by reducing STAT3 phosphorylation .

PLG upregulates P53 signaling in vivo and in vitro .

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

Deletion of MDM2, an inhibitor of P53, in osteoblast lineage cells leads to increased P53 production, which in turn inhibits bone organogenesis and homeostasis.

In conclusion, PLG attenuates high calcium and phosphate induced vascular calcification by upregulating P53 and PTEN signaling in VSMCs.

The main findings of the present study indicated that (1) PLG is a promising natural herbal extract for the management of vascular calcification and that (2) PLG attenuates high calcium- and phosphate induced vascular calcification by preserving P53 and PTEN signaling in VSMCs.

In conclusion, PLG attenuates high calcium and phosphate induced vascular calcification by upregulating P53 and PTEN signaling in VSMCs.

The main findings of the present study indicated that (1) PLG is a promising natural herbal extract for the management of vascular calcification and that (2) PLG attenuates high calcium- and phosphate induced vascular calcification by preserving P53 and PTEN signaling in VSMCs.

Thus, while p53 deletion and missense mutations can enhance mTOR, emphasizing the functional interplay between AMPK and wild-type p53, some mutants can display effects on the canonical AMPK-mTOR signaling beyond the transcriptional repression.

By promoting glucose uptake, mutant p53 can limit autophagy dependent energy production.

Thus, while mutant p53 enhanced glucose metabolism can correspondingly suppressed autophagy in proliferating cancer cells, it is reasonable that a reduced glycolysis by mutant p53 can induce autophagy in quiescent cells.

This is in fact in line with the observations that CHIP, beyond targeting wild-type p53 by K48 polyubiquitinition, preferentially degrades aggregation prone mutant p53 proteins through K63 polyubiquitinition chains.

Although p21 expression generally contributes to the induction of an irreversible proliferative arrest, transient p53 mediated induction of p21 is reversible, allowing cells to re-enter the cell cycle once stress or damage has been resolved.

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

Therefore, it is reasonable that some mutant p53 forms may enhance autophagy required to prevent energy crisis and maintain nucleotide pools during starvation in cancer cells caused by hypoxia and nutrition depletion in tumor microenvironment.

Alternatively, the mutant p53 driven autophagy suppressive function might be overridden by additional signaling, mutations or epigenetic changes.

Secondly, while mutant p53 have been linked to promote glycolysis through distinct mechanisms, emerging data supports the notion that not all mutants display enhanced glycolysis.

Therefore, sophisticated animal studies are needed for tumors that have undergone mutant p53 induced EMT program to provide an in vivo correlate in preclinical models.

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

The precise mechanism of how LASP1 promotes PTEN ubiquitination still remains elusive 53.

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.

One study showed that Nuclear Receptor Binding SET Domain Protein 2 (NSD2)-mediated dimethylation of PTEN promotes 53BP1 interactions and subsequent recruitment to sites of DNA-damage sites 75.

Newer studies add to this small body of data , including an intriguing study where a novel PTEN / ARID4B / PI3K pathway in which PTEN inhibits the expression of ARID4B was characterised .

PTEN inhibits ARID4B expression and thus prevents the transcriptional activation of ARID4B transcriptional targets PIK3CA and PIK3R2 ( PI3K subunits ) 79 .

By using specific mutants of PTEN lacking lipid phosphatase function, an early study concluded that PTEN may block cell migration through a protein phosphatase mediated function on focal adhesion kinase (FAK) protein 14.

PTEN and PDHK1 were observed to have a synthetic-lethal relationship, as loss of PTEN and upregulation of PDHK1 in cells induced glycolysis and a dependency on PDHK1 100.

This PTEN/ARID4B/PI3K signalling axis identifies a novel player in the PTEN mediated suppression of the PI3K pathway and provides a new opportunity to design novel therapeutics to target this axis to promote the tumour suppressive functions of PTEN.

In one of these studies, Baker et al. reported that Notch1 can mediate transcriptional suppression of PTEN, resulting in the derepression of PI3K signalling and development of trastuzumab resistance 91.

This study was the first to link the Ras-MAPK and PI3K pathways through Notch1 transcriptional suppression of PTEN 91.

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.

It was reported that PTEN could dephosphorylate PGK1, a glycolytic enzyme and protein kinase with a tumorigenic role in glioblastoma 99.

Dephosphorylation of PGK1 by PTEN was found to inhibit its activity, downstream glycolytic functions, and glioblastoma cell proliferation 99, thereby presenting another mechanism in which PTEN functions as a tumour suppressor.

Newer studies add to this small body of data, including an intriguing study where a novel PTEN/ARID4B/PI3K pathway in which PTEN inhibits the expression of ARID4B was characterised.

PTEN inhibits ARID4B expression and thus prevents the transcriptional activation of ARID4B transcriptional targets PIK3CA and PIK3R2 (PI3K subunits) 79.

Furthermore, nuclear PTEN directly interacted with and inhibited RNA polymerase II (RNAPII)-mediated transcription, where it was involved in direct downregulation of critical transcriptional control genes including AFF4 and POL2RA 80.

Colocalisation of PTEN and PTENalpha promoted the function of PINK1, a mitochondrial-target kinase, and subsequently promoted energy production 105.

It is known that AKT signaling plays a critical role in the regulation of pre-mRNA splicing 77 and PTEN has been shown to modulate G6PD pre-mRNA splicing in an AKT independent manner 78.

Numb inhibits Notch1, leading to the downregulation of RBP-Jkappa 94, which upregulates PTEN and anti-EMT effectors, leading to the downregulation of p-FAK and pro EMT effectors 94.

Down-regulated of RAC1 expression or loss of its function significantly suppressed cancer cell proliferation and metastasis.

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.

Additionally, IR could enhance the expression and activation of RAC1, positively associated with the up-regulation of PAK1, p-PAK1, LIMK1, p-LIMK1, Cofilin and p-Cofilin.

In this report, we found that IR could induce the up-regulation of RAC1 expression and activity via activating the PI3K and AKT signaling pathway.

IR significantly promoted the expression of GST-RAC1, RAC1, PAK1, p-PAK1, LIMK1, p-LIMK1, Cofilin, and p-Cofilin in the cells treated with IR.

These results indicate that IR increases the expression and activity of Rac1 via activating the PI3K and AKT signaling pathway.

A question is how IR induces Rac1 expression.

In addition, as shown in XREF_FIG, the results of GST-pull down assays showed Rac1 expression and activity was significantly increased after 6 Gy dose of IR in lung cancer cells, suggesting that IR could promote the Rac1 expression and activity.

IR Induces RAC1 Expression and EMT in Lung Cancer Cells.

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 ).

Consistent with the in vitro results, RAC1 significantly enhanced tumor xenograft growth treated with IR (XREF_FIG).

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 .

The western blot results showed that IR could significantly increase the PI3K, p-AKT, AKT, and RAC1, whereas the LY294002 reversed this effect in both A549 and PC9 cells (XREF_FIG).

Furthermore, IR induced RAC1 expression and activity via the activation of PI3K and 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.

In this study, we also found that overexpression of Rac1 significantly promoted the migration and invasion, and radioresistance of lung cancer cells, whereas the knockdown of Rac1 markedly inhibited these capabilities of lung cancer cells in vivo and in vitro.

In this article, we uncovered inhibition of RAC1 in lung cancer cells is sufficient to abrogate the IR induced and RAC1 mediated tumor migration and invasion, as evidenced by cell proliferation, colony formation, and Transwell assay.

RAC1 Promotes Radioresistance, Invasion and Migration in Lung Cancer Cells.

As exhibited in XREF_FIG, 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.

As exhibited in XREF_FIG, 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.

The colony formation assays showed that ectopic overexpression of RAC1 promoted growth of both A549 and PC9 cells compared to empty vector control (XREF_FIG).

The results demonstrated that RAC1 increased survival capacity of A549 and PC9 cells after IR at 0, 2, 4, 6, and 8 Gy (XREF_FIG).

These results suggest that RAC1 promotes proliferation of lung cancer cells.

Furthermore, CCK-8 assays demonstrated that overexpression of RAC1 promoted cell proliferation, but silencing of RAC1 expression inhibited cell proliferation in both A549 and PC9 cells (XREF_FIG).

Furthermore, IR induced RAC1 expression and activity via the activation of PI3K and 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.

Collectively, we further found that RAC1 enhanced radioresistance by promoting EMT via targeting the PAK1-LIMK1-Cofilins signaling in lung cancer.

Silencing Rac1 significantly inhibited the EMT phenotype in lung cancer cells, accompanied with a significant down-regulation of RAC1, PAK1, p-PAK1, LIMK1, p-LIMK1, Cofilin, and p-Cofilin in lung cancer cells.

Our previous study found that RAC1 could significantly induce the EMT of colon cancer cells, which may be related to the positive regulation of Rac1/PAK1/LIMK1/Cofilins signaling pathway.

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 .