Adhesion tyrosine kinase

Fyn is a nonreceptor tyrosine kinase related to Src that is frequently found in cell junctions. Die protein is N-myristoylated and palmitoylated and thereby becomes associated with caveolae-like membrane microdomains. Fyn can interact with a variety of other signaling molecules and control a diversity of biological processes such as T cell receptor signaling, regulation of brain function, and adhesion mediated signaling. 

Fak (focal adhesion kinase) is expressed in most tissues and is evolutionary conserved across species. It is activated by integrin clustering and by stimulation of several G protein-coupled recqrtors and RTKs. Fak is associated with focal adhesions and regulates cell spreading and migration. The kinase is essential for embryonic development since the homozygote Fak knockout is embryonic lethal. Pyk2 (proline-rich tyrosine kinase 2), the second member of the Fak kinase family has a more restricted expression pattern (primarily neuronal and hematopoietic cells) and does not localize to focal adhesions. 

Li H, Wong WS. Pertussis toxin activates tyrosine kinase signaling cascade in myelomonocytic cells a mechanism for cell adhesion. Biochem Biophys Res Commun 2001 283(5) 1077-1082. 

Integrins present in focal adhesion complexes cause the recruitment of two types of protein tyrosine kinases to the plasma membrane focal adhesion kinase (FAK) and Src. They play a role in cell survival and proliferation. 

Downstream in the pathway of rescue, PKB effects a number of phosphorylations that prevent apoptosis (Figure 8.17) (see Section 8.2 3.2). It is of interest to note that both growth factor receptors, such as TrkA, and adhesion molecules generate rescue signals through activation of protein tyrosine kinases, and apparently cells require both attachment to extracellular matrix and the presence of a particular growth factor in order not to die. 

In addition, the phosphotyrosine moiety (Y402) on a proline-rich tyrosine kinase (PYK2, a NRPTK) can apparently compete with phosphoY527 for interaction with SH2 domain on Src and lead to Src activation. PYK2 is a member of the Fak family. It is highly expressed in the nervous system. Its activation depends on both cell adhesion and the presence of calcium or PKC activation. Therefore, certain G-protein-coupled receptors (GPCRs)... 

Parson, IT, and Parson, S.J. Src family protein tyrosine kinases cooperating with growth factor and adhesion signaling pathways (1997) Curr. Op. Cell Biol. 9, 187-192... 

Collaborative signaling integrin-mediated cell adhesion modulates signal transduction by other receptors (e.g., receptor tyrosine kinases). 

The integrins do not have any enzyme activity in their own cytoplasmic domain, but on hgand binding, stimulation of tyrosine phosphorylation is observed on the cytoplasmic side of many cells, such as fibroblasts and platelets. The exact configuration of protein-protein interactions on the cytosolic side of the integrins is not clear and the mechanism of stimulation of protein tyrosine kinases is unknown. Some components of the focal adhesion points, such as the structural protein tensin, have SH2 and SH3 domains that may serve as specific attachment points for tyrosine kinases and other signal proteins. 

Fig. 3. A simplified illustration of BCR-ABL and SRC family kinase involvement in oncogenic signaling pathways. The inhibitory effect is indicated by the upside-down T s. ABL = Abelson tyrosine kinase BCR = breakpoint cluster region FAK = focal adhesion kinase Grb-2 = growth factor receptor-bound protein 2 HcK = hematopoietic cell kinase JNK = Jun amino-terminal kinase P = phosphate group PI3 K = phosphatidylinositol-3-kinase SFK = SRC family kinases StatS = signal transducer and activator of transcription 5. (Reprinted with permission from Ref (123)). 

Boutahar N, Guignandon A, Vico L, Lafage-Proust MH. 2004. Mechanical strain on osteoblasts activates autophosphorylation of focal adhesion kinase and proline-rich tyrosine kinase-2 tyrosine sites involved in ERK activation. J Biol Chem 279 30588-99. 

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