Akt1 promotes focal adhesion disassembly and cell motility through phosphorylation of FAK in growth factor-stimulated cells

Higuchi, Masakazu; Kihara, Rina; Okazaki, Tomohiko; Aoki, Ichiro; Suetsugu, Shiro; Gotoh, Yukiko

doi:10.1242/jcs.112722

Cited by 30 publications

(32 citation statements)

References 48 publications

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“…phosphorylation of FAK at Tyr 397 (Higuchi et al, 2013). However, we find no evidence that LAR regulates FAK activity and phosphorylation of CDK1 Thr 161 in LARΔP cells is not affected by PDGF (Fig.…”

Section: Discussionmentioning

confidence: 57%

LAR protein tyrosine phosphatase regulates focal adhesions through CDK1

Sarhan

Patel

Cowell

et al. 2016

Journal of Cell Science

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Focal adhesions are complex multi-molecular structures that link the actin cytoskeleton to the extracellular matrix through integrin adhesion receptors and play a key role in regulation of many cellular functions. LAR (also known as PTPRF) is a receptor protein tyrosine phosphatase that regulates PDGF signalling and localises to focal adhesions. We have observed that loss of LAR phosphatase activity in mouse embryonic fibroblasts results in reduced numbers of focal adhesions and decreased adhesion to fibronectin. To understand how LAR regulates cell adhesion we used phosphoproteomic data, comparing global phosphorylation events in wild-type and LAR phosphatase-deficient cells, to analyse differential kinase activity. Kinase prediction analysis of LAR-regulated phosphosites identified a node of cytoskeleton-and adhesion-related proteins centred on cyclin-dependent kinase-1 (CDK1). We found that loss of LAR activity resulted in reduced activity of CDK1, and that CDK1 activity was required for LAR-mediated focal adhesion complex formation. We also established that LAR regulates CDK1 activity through c-Abl and Akt family proteins. In summary, we have identified a new role for a receptor protein tyrosine phosphatase in regulating CDK1 activity and hence cell adhesion to the extracellular matrix.

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Section: Discussionmentioning

confidence: 57%

LAR protein tyrosine phosphatase regulates focal adhesions through CDK1

Sarhan

Patel

Cowell

et al. 2016

Journal of Cell Science

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“…This contrasts with the classical view of this pathway in which FAK is an upstream component of the pathway and largely insensitive to PI3K (7,8,10). However, recent reports have independently shown that serine/threonine phosphorylation of FAK by Akt, a major effector of PI3K, enhances its activation (53,54). Our results provide a plausible explanation for this apparent discrepancy in the literature because we showed that FAK becomes sensitized to PI3K-Akt regulation only when GIV enhances this pathway above a critical threshold.…”

Section: Discussionmentioning

confidence: 62%

GIV/Girdin (Gα-interacting, Vesicle-associated Protein/Girdin) Creates a Positive Feedback Loop That Potentiates Outside-in Integrin Signaling in Cancer Cells

Leyme

Marivin

Garcia‐Marcos

2016

Journal of Biological Chemistry

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Activation of the tyrosine kinase focal adhesion kinase (FAK) upon cell stimulation by the extracellular matrix initiates integrin outside-in signaling. FAK is directly recruited to active integrins, which enhances its kinase activity and triggers downstream signaling like activation of PI3K. We recently described that G␣-interacting, vesicle-associated protein (GIV), a protein up-regulated in metastatic cancers, is also required for outside-in integrin signaling. More specifically, we found that GIV is a non-receptor guanine nucleotide exchange factor that activates trimeric G proteins in response to integrin stimulation to enhance PI3K signaling and tumor cell migration. In contrast, previous reports have established that GIV is involved in phosphotyrosine (Tyr(P))-based signaling in response to growth factor stimulation; i.e. GIV phosphorylation at Tyr-1764 and Tyr-1798 recruits and activates PI3K. Here we show that phosphorylation of GIV at Tyr-1764/Tyr-1798 is also required to enhance PI3K-Akt signaling and tumor cell migration in response to integrin stimulation, indicating that GIV functions in Tyr(P)-dependent integrin signaling. Unexpectedly, we found that activation of FAK, an upstream component of the integrin Tyr(P) signaling cascade, was diminished in GIV-depleted cells, suggesting that GIV is required to establish a positive feedback loop that enhances integrin-FAK signaling. Mechanistically, we demonstrate that this feedback activation of FAK depends on both guanine nucleotide exchange factor and Tyr(P) GIV signaling as well as on their convergence point, PI3K. Taken together, our results provide novel mechanistic insights into how GIV promotes proinvasive cancer cell behavior by working as a signal-amplifying platform at the crossroads of trimeric G protein and Tyr(P) signaling.

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“…In addition, we found that treatment with pan-EGFR inhibitors also resulted in down regulation of cell cycle key regulators such as Cyclin D1 and Cyclin A, implicating that down regulation of ERK1/2 and AKT pathways affects cell cycle progression. Moreover, a recent study has exemplified the novel function of AKT which promotes FAK auto-phosphorylation for cell migration and motility [49]. Together these results indicate that canertinib affects both the proliferative (ERK) and survival (AKT) pathways.…”

Section: Discussionmentioning

confidence: 89%

Targeting EGF-receptor(s) - STAT1 axis attenuates tumor growth and metastasis through downregulation of MUC4 mucin in human pancreatic cancer

et al. 2014

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Transmembrane proteins MUC4, EGFR and HER2 are shown to be critical in invasion and metastasis of pancreatic cancer. Besides, we and others have demonstrated de novo expression of MUC4 in ~70-90% of pancreatic cancer patients and its stabilizing effects on HER2 downstream signaling in pancreatic cancer. Here, we found that use of canertinib or afatinib resulted in reduction of MUC4 and abrogation of in vitro and in vivo oncogenic functions of MUC4 in pancreatic cancer cells. Notably, silencing of EGFR family member in pancreatic cancer cells decreased MUC4 expression through reduced phospho-STAT1. Furthermore, canertinib and afatinib treatment also inhibited proliferation, migration and survival of pancreatic cancer cells by attenuation of signaling events including pERK1/2 (T202/Y204), cyclin D1, cyclin A, pFAK (Y925) and pAKT (Ser473). Using in vivo bioluminescent imaging, we demonstrated that canertinib treatment significantly reduced tumor burden (P=0.0164) and metastasis to various organs. Further, reduced expression of MUC4 and EGFR family members were confirmed in xenografts. Our results for the first time demonstrated the targeting of EGFR family members along with MUC4 by using pan-EGFR inhibitors. In conclusion, our studies will enhance the translational acquaintance of pan-EGFR inhibitors for combinational therapies to combat against lethal pancreatic cancer.

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Akt1 promotes focal adhesion disassembly and cell motility through phosphorylation of FAK in growth factor-stimulated cells

Cited by 30 publications

References 48 publications

LAR protein tyrosine phosphatase regulates focal adhesions through CDK1

LAR protein tyrosine phosphatase regulates focal adhesions through CDK1

GIV/Girdin (Gα-interacting, Vesicle-associated Protein/Girdin) Creates a Positive Feedback Loop That Potentiates Outside-in Integrin Signaling in Cancer Cells

Targeting EGF-receptor(s) - STAT1 axis attenuates tumor growth and metastasis through downregulation of MUC4 mucin in human pancreatic cancer

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