Tyrosine phosphorylation of type Iγ phosphatidylinositol phosphate kinase by Src regulates an integrin–talin switch

Ling, Kun; Doughman, Renee L.; Iyer, Vidhya V.; Firestone, Ari J.; Bairstow, Shawn F.; Mosher, Deane F.; Schaller, Michael D.; Anderson, Richard A.

doi:10.1083/jcb.200310067

Cited by 135 publications

(217 citation statements)

References 33 publications

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Section: Role Of Pipkic661mentioning

confidence: 99%

“…PIPKIg661 is phosphorylated at tyrosine 644 within the unique tail by SFKs, although in vivo FAK functions to promote tyrosine phosphorylation of PIPKIg661 by Src (Di Paolo et al, 2002;Ling et al, 2002Ling et al, , 2003. This phosphorylation event is important for the efficient association of PIPKIg661 with talin and for localization to focal adhesions (Ling et al, 2003). Phosphatidyl inositol 4,5-bisphosphate (PIP 2 ), which is the product generated by phosphorylation of PIP by PIP kinases, regulates the interactions between a number of cytoskeletal proteins, including the association of talin with the cytoplasmic domains of the integrin b subunits and the binding of vinculin to talin (Nayal et al, 2004).…”

Section: Role Of Pipkic661mentioning

confidence: 99%

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The interplay between Src and integrins in normal and tumor biology

2004

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Src family nonreceptor protein tyrosine kinases transduce signals that control normal cellular processes such as cell proliferation, adhesion and motility. Normally, cellular Src is held in an inactive state, but in several cancer types, abnormal events lead to elevated kinase activity of the protein and cause pleiotropic cellular responses inducing transformation and metastasis. A prerequisite of the ability of a cancer cell to undergo metastasis into distant tissues is to penetrate surrounding extracellular matrices. These processes are facilitated by the integrin family of cell adhesion molecules. As is the case with Src, altered integrin activity or substrate affinity can contribute to the neoplastic phenotype. Therefore, understanding the interplay between Src and integrin function has been of intense interest over the past few years. This review focuses on the role of Src and integrin signaling in normal cells and how this is deregulated in human cancer. We will identify the key players in the integrin-mediated signaling pathways involved in cell motility and apoptosis, such as FAK, paxillin and p130 CAS , and discuss how Src signaling affects the formation of focal adhesions and the extracellular matrix.

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Section: Role Of Pipkic661mentioning

confidence: 99%

Section: Role Of Pipkic661mentioning

confidence: 99%

The interplay between Src and integrins in normal and tumor biology

2004

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“…To assess whether talin binding was sufficient for trans-dominant inhibition, we examined the effect of cellular expression of PIPKI␥-90, a talin-binding splice variant of PIPKI␥ (41, 49), on integrin activation. PIPKI␥-90 binds to talin at a site within the F3 subdomain of talin (41) that overlaps with the integrin-binding site (50,51). Furthermore, PIPKI␥-90 can compete with integrin ␤ tails for binding to talin (50,51).…”

Section: Expression Of Talin-binding Variants Of Pipki␥ Inhibits Intementioning

confidence: 99%

“…PIPKI␥-90 binds to talin at a site within the F3 subdomain of talin (41) that overlaps with the integrin-binding site (50,51). Furthermore, PIPKI␥-90 can compete with integrin ␤ tails for binding to talin (50,51). To test the hypothesis that competition for talin would lead to trans-dominant inhibition, the effect of GFP fusions of the talin-binding splice variant, PIPKI␥-90, and the non-binding variant, PIPKI␥-87, on integrin activation were assessed by flow cytometry.…”

Section: Expression Of Talin-binding Variants Of Pipki␥ Inhibits Intementioning

confidence: 99%

Competition for Talin Results in Trans-dominant Inhibition of Integrin Activation

Calderwood

Tai

Paolo

et al. 2004

Journal of Biological Chemistry

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The ability of integrin adhesion receptors to undergo rapid changes in affinity for their extracellular ligands (integrin activation) is essential for the development and function of multicellular animals and is dependent on interactions between the integrin ␤ subunit-cytoplasmic tail and the cytoskeletal protein talin. Cross-talk among different integrins and between integrins and other receptors impacts many cellular processes including adhesion, spreading, migration, clot retraction, proliferation, and differentiation. One form of integrin cross-talk, transdominant inhibition of integrin activation, occurs when ligand binding to one integrin inhibits the activation of a second integrin. This may be relevant clinically in a number of settings such as during platelet adhesion, leukocyte trans-migration, and angiogenesis. Here we report that competition for talin underlies the trans-dominant inhibition of integrin activation. This conclusion is based on our observations that (i) ␤ tails selectively defective in talin binding are unable to mediate trans-dominant inhibition, (ii) trans-dominant inhibition can be reversed by overexpression of integrin binding and activating fragments of talin, and (iii) expression of another non-integrin talin-binding protein, phosphatidylinositol phosphate kinase type I␥-90, also inhibits integrin activation. Thus, the sequestration of talin by the suppressive species is both necessary and sufficient for trans-dominant inhibition of integrin activation.

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“…Equally important is understand whether signals initiated by binding of apoptotic cells alter the ability of talin to bind the β5 cytoplasmic tail. This could be at the level of either talin or a sequencespecific motif in the β5 cytoplasmic tail, and maybe tiggered by post-translational modifications [41], competition by intracellular signaling molecules [41], or by activation of a specific GTPase such as Rac1 or RhoG [16]. We have shown that αvβ5 integrin is part of a signaling pathway with the Mertk, which culminates in the association of tyrosine phosphorylated FAK with the β5 cytoplasmic tail [35].…”

Section: Discussionmentioning

confidence: 91%

A NPxY-independent β5 integrin activation signal regulates phagocytosis of apoptotic cells

Singh

D’Mello

Henegouwen

et al. 2007

Biochemical and Biophysical Research Communications

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Integrin receptors are heterodimeric trans-membrane receptors with critical functions in cell adhesion and migration, cell cycle progression, differentiation, apoptosis, and phagocytosis of apoptotic cells. Integrins are activated by intracellular signaling that alter the binding affinity for extracellular ligands, so-called inside to outside signaling. A common element for integrin activation involves binding of the cytoskeletal protein talin, via its FERM domain, to a highly conserved NPxY motif in the beta chain cytoplasmic tails, which is involved in long-range conformation changes to the extracellular domain that impinges on ligand affinity. When the human beta-5 (β5) integrin cDNA was expressed in αv positive, β5 and β3 negative hamster CS-1 cells, it promoted NPxY-dependent adhesion to VTN-coated surfaces, phosphorylation of FAK, and concomitantly, β5 integrin-EGFP protein was recruited into talin and paxillin-containing focal adhesions. Expression of a NPxY destabilizing β5 mutant (Y750A) abrogated adhesion and β5-Y750A-EGFP was excluded from focal adhesions at the tips of stress fibers. Surprisingly, expression of β5 Y750A integrin had a potent gainof-function effect on apoptotic cell phagocytosis, and further, a β5-Y750A EGFP fusion integrin readily bound MFG-E8-coated 10 um diameter microspheres developed as apoptotic cell mimetics. The critical sequences in β5 integrin were mapped to a YEMAS motif just proximal to the NPxY motif. Our studies suggest that the phagocytic function of β5 integrin is regulated by an unconventional NPxY-talin independent activation signal and argue for the existence of molecular switches in the β5 cytoplasmic tail for adhesion and phagocytosis.

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Tyrosine phosphorylation of type Iγ phosphatidylinositol phosphate kinase by Src regulates an integrin–talin switch

Cited by 135 publications

References 33 publications

The interplay between Src and integrins in normal and tumor biology

The interplay between Src and integrins in normal and tumor biology

Competition for Talin Results in Trans-dominant Inhibition of Integrin Activation

A NPxY-independent β5 integrin activation signal regulates phagocytosis of apoptotic cells

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