Phosphatidylinositol 3-kinase signals activate a selective subset of Rac/Rho-dependent effector pathways

Rei, Karin; Nobes, Catherine D.; Thomas, George; Hall, Alan; Cantrell, Doreen A.

doi:10.1016/s0960-9822(96)00749-x

Cited by 254 publications

(231 citation statements)

References 57 publications

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“…In this context, PTEN induced T lymphomas are invasive tumors that originate in the thymus but cause morbidity when they disseminate to the periphery and extensively infiltrate multiple tissues including the spleen, liver, kidney, and bone marrow (Suzuki et al, 2001;Hagenbeek et al, 2004). The previous idea of how PTEN might control cell adhesion and motility is that PI(3,4,5)P 3 signaling regulates the GTPases Rac and RhoA and coordinates actin and microtubule dynamics (Reif et al, 1996;Liliental et al, 2000). PTEN also has protein phosphatase activity that inhibits cell motility (Raftopoulou et al, 2004;Leslie et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Phosphoinositide-dependent kinase 1 controls migration and malignant transformation but not cell growth and proliferation in PTEN-null lymphocytes

Finlay¹,

Sinclair²,

Feijóo³

et al. 2009

J Cell Biol

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Section: Discussionmentioning

confidence: 99%

Phosphoinositide-dependent kinase 1 controls migration and malignant transformation but not cell growth and proliferation in PTEN-null lymphocytes

Finlay¹,

Sinclair²,

Feijóo³

et al. 2009

J Cell Biol

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“…Growth factors such as EGF have been shown to activate the JNK pathway through PI3K (Logan et al, 1997). Overexpression of PI3K catalytic subunit (p110) can lead to Rac activation (Klippel et al, 1996;Minden et al, 1995;Minden and Karin, 1997) and its expression in COS cells was shown to induce activation of JNK (Rei et al, 1996). Taken together these data suggest that the PI3K activated pathway could be similarly involved in coupling Rac signalling to stress activated kinases.…”

Section: Introductionmentioning

confidence: 86%

Gas6-mediated survival in NIH3T3 cells activates stress signalling cascade and is independent of Ras

et al. 1999

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“…Increased production of D-3 phosphoinositides by PI3K contributes to an integrin-mediated pathway activating Rac to promote cell spreading (13,50,51,55), and both PI3K and PLC-␥1 have been implicated as major effector molecules promoting cell motility following activation of receptor protein-tyrosine kinases (12,35). Finally, Src phosphorylation of FAK itself, in addition to promoting focal adhesion turnover through FAK degradation as discussed above, could also conceivably stimulate cell migration through FAK Tyr-925 phosphorylation.…”

Section: F397-fakmentioning

confidence: 98%

Induced Focal Adhesion Kinase (FAK) Expression in FAK-Null Cells Enhances Cell Spreading and Migration Requiring Both Auto- and Activation Loop Phosphorylation Sites and Inhibits Adhesion-Dependent Tyrosine Phosphorylation of Pyk2

Owen

Ruest

Fry³

et al. 1999

Molecular and Cellular Biology

369

355

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Focal adhesion kinase (FAK) is a nonreceptor protein tyrosine kinase involved in integrin-mediated control of cell behavior. Following cell adhesion to components of the extracellular matrix, FAK becomes phosphorylated at multiple sites, including tyrosines 397, 576, and 577. Tyr-397 is an autophosphorylation site that promotes interaction with c-Src or Fyn. Tyr-576 and Tyr-577 lie in the putative activation loop of the kinase domain, and FAK catalytic activity may be elevated through phosphorylation of these residues by associated Src family kinase. Recent studies have implicated FAK as a positive regulator of cell spreading and migration. To further study the mechanism of adhesion-induced FAK activation and the possible role and signaling requirements for FAK in cell spreading and migration, we utilized the tetracycline repression system to achieve inducible expression of either wild-type FAK or phosphorylation site mutants in fibroblasts derived from FAKnull mouse embryos. Using these Tet-FAK cells, we demonstrated that both the FAK autophosphorylation and activation loop sites are critical for maximum adhesion-induced FAK activation and FAK-enhanced cell spreading and migration responses. Negative effects on cell spreading and migration, as well as decreased phosphorylation of the substrate p130 Cas , were observed upon induced expression of the FAK autophosphorylation site mutant. These negative effects appear to result from an inhibition of integrin-mediated signaling by the FAKrelated kinase Pyk2/CAK␤/RAFTK/CadTK. FAK (focal adhesion kinase) is a widely expressed nonreceptor protein tyrosine kinase found in focal adhesions of cultured cells (23,61). FAK becomes activated by tyrosine phosphorylation in response to integrin clustering achieved by cell adhesion or antibody cross-linking (5,19,23,34,40). FAK Tyr-397 is an autophosphorylation site and a high-affinity binding site for Src homology 2 (SH2) domains of Src family kinases, including c- Src and Fyn (48,62,80). This interaction could contribute both to the recruitment of Src family kinases to sites of cell adhesion and to their catalytic activation through C-terminal tail displacement. Other adhesion-regulated sites of FAK phosphorylation are tyrosines 407, 576, 577, 861, and 925 (7, 8, 65). These tyrosines do not appear to be autophosphorylation sites but are efficiently phosphorylated by c-Src in vitro and elevated in Src-transformed cells (7,8,66). Tyr-397 can also be phosphorylated by c-Src (7); hence, it is not strictly an autophosphorylation site. Tyr-576 and Tyr-577 lie in the putative activation loop of the kinase domain, and mutation of these residues reduces FAK catalytic activity (7, 42). The potential for reciprocal activation of FAK and Src family kinases suggests a mechanism for signal amplification following an initial integrin-induced FAK autophosphorylation event. Other sites of FAK tyrosine phosphorylation are likely to participate in downstream signaling through recruitment of additional SH2-containing proteins. Indeed, phosphoryl...

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Phosphatidylinositol 3-kinase signals activate a selective subset of Rac/Rho-dependent effector pathways

Abstract: Our results demonstrate that PI 3-kinase induces a selective subset of cellular responses, but is not sufficient to stimulate the full repertoire of Rac- or Rho-mediated responses.

Cited by 254 publications

References 57 publications

Phosphoinositide-dependent kinase 1 controls migration and malignant transformation but not cell growth and proliferation in PTEN-null lymphocytes

Phosphoinositide-dependent kinase 1 controls migration and malignant transformation but not cell growth and proliferation in PTEN-null lymphocytes

Gas6-mediated survival in NIH3T3 cells activates stress signalling cascade and is independent of Ras

Induced Focal Adhesion Kinase (FAK) Expression in FAK-Null Cells Enhances Cell Spreading and Migration Requiring Both Auto- and Activation Loop Phosphorylation Sites and Inhibits Adhesion-Dependent Tyrosine Phosphorylation of Pyk2

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