Trends in Cell Biology
Integrin signalling and tyrosine phosphorylation: just the FAKs?
Section snippets
Integrin activation of Abl, Syk and c-Src
In fibroblasts, fibronectin stimulation promotes c-Abl PTK translocation from the nucleus to the cytoplasm, where it becomes transiently activated and associated with integrin clusters[1]. As first shown in platelets, collagen or fibrinogen stimulation can stimulate the Syk PTK[2]where its activity is regulated by Src-family PTKs[3]. Members of the Src PTK family (such as c-Src and Fyn) have been implicated as playing a primary role in integrin signalling events because v-Src or constitutively
The FAK PTK
FAK colocalizes with integrins at cell–substratum contact sites, and its PTK activity is enhanced by cellular binding to ECM proteins[8]. Consequently, FAK has been proposed to play a central role in integrin-stimulated signalling events. This hypothesis is supported by gene-knockout results—both fibronectin- and FAK-deficient mice die from similar developmental gastrulation defects, suggesting that FAK transduces fibronectin-initiated signals into cells[11].
FAK homologues have been identified
FAK and Pyk2 form a PTK subfamily
FAK and a second non-receptor PTK, variously called proline-rich tyrosine kinase 2 (Pyk2), cell-adhesion kinase β (CAKβ), related adhesion focal tyrosine kinase (RAFTK) or calcium-dependent protein-tyrosine kinase (CADTK), define a new subfamily of non- receptor PTKs. To avoid nomenclature confusion, we will refer to this FAK-related protein as Pyk2. Pyk2 is highly expressed in cells of the central nervous system and in cells of haematopoietic lineage. Pyk2 (112 kDa) is slightly smaller than FAK
FAK and Pyk2 connections to p130Cas
The large adaptor protein p130Cas has been implicated in integrin-mediated signalling events involving both FAK and Pyk2 (Ref. [29]) owing to its SH3-mediated binding interactions with either of two proline-rich motifs in the FAK C-terminal domain[8]. Although p130Cas binds to FAK, and its tyrosine phosphorylation parallels that of FAK after integrin stimulation in fibroblasts, the PTK that phosphorylates p130Cas might not necessarily be FAK or Pyk2 (Ref. [30]). In FAK-deficient fibroblasts,
Signals downstream of p130Cas tyrosine phosphorylation
What signals could be generated as a result of p130Cas family tyrosine phosphorylation? Integrin stimulation promotes the binding of the Crk[31]and Nck[33]SH3–SH2 adaptor proteins to p130Cas. Although both Crk and Nck bind to the Sos GDP–GTP exchange factor (GEF) that activates Ras and the ERK mitogen-activated protein (MAP) kinase pathway, integrin-stimulated p130Cas tyrosine phosphorylation might not be tightly linked to ERK activation. In Src− fibroblasts, where p130Cas is not appreciably
Multiple integrin signalling pathways to ERK MAP kinase
In contrast to integrin-stimulated signalling to JNK, a considerable amount is known about integrin connections to the activation of the ERK MAP kinase pathway (Fig. 3). The first link between integrin-stimulated tyrosine phosphorylation and signalling to ERK was the demonstration that the Grb2 adaptor protein binds through its SH2 domain to a conserved site in the FAK C-terminal domain [(p)Tyr925-E-N-V motif] after fibronectin stimulation of fibroblasts[42]. Grb2 recruitment of the Sos GDP–GTP
Targets for integrin-activated ERK MAP kinase
Integrin-activated ERK translocates to the nucleus and can phosphorylate transcription factors such as Elk1 and c-Myc. The ability of activated ERK to phosphorylate transcription factors could explain some of the known gene-induction responses to ECM-mediated adhesion[49]. Activated ERK can phosphorylate cytoplasmic proteins such as phospholipase A2 (Ref. [50]), and ERK2 signals also act to decrease integrin receptor ligand-binding affinity, thus providing a negative-feedback loop[51].
Role of FAK in cell migration
Both growth factors and integrins can stimulate FAK tyrosine phosphorylation under conditions that promote cell migration. Although FAK was believed originally to be involved in the process of cell–substratum contact site formation, as its name implies, recent studies have shown that this might not be correct[56]. FAK− cells exhibit decreased integrin-stimulated cell migration responses, potentially owing to the elevated number of cell–substratum contacts formed[11]. For this reason, it has
Perspectives
Most studies on integrin-based signalling have used acute cell stimulation either by plating detached cells on extracellular matrix proteins or by antibody- or synthetic ligand-induced integrin receptor clustering. Conditions of this sort will be found rarely in vivo, except perhaps for cells leaving the circulation or at the leading edge of migrating cells. Yet it is clear that occupied integrins in immotile or quiescent cells must be generating some type of as-yet-unknown signal since
Acknowledgements
We thank our colleagues for sharing results prior to publication. Space limitation has precluded citation of many primary references, which are included in reviews cited. Work in our laboratories is supported by grants from the National Cancer Institute and the American Cancer Society. Tony Hunter is an American Cancer Society research professor.
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