Focal adhesion kinase

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. 

Cicala C, Arthos J, Ruiz M, et al. Induction of phosphorylation and intracellular association of CC chemokine receptor 5 and focal adhesion kinase in primary human CD4+ T cells by macrophage-tropic HIV envelope. J Immunol 1999 163(l) 420-426. 

Cicala C, Arthos J, Rubbert A, et al. HIV-1 envelope induces activation of caspase-3 and cleavage of focal adhesion kinase in primary human CD4(+) T cells. Proc Natl Acad Sci U S A 2000 97(3) 1178-1183. 

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. 

FIGURE 7-3 Integrins are heterodimers. Integrins consist of a and 3 subunits noncovalently linked, which interact via their cytoplasmic domains with a number of cytoplasmic proteins. The axpi integrin complex on the left binds to a complex which includes focal adhesion kinase (FAK). The a6P4 integrin complex contains fibronectin (FN) III repeats, which mediate binding to intermediate filaments. 

Protein kinase Cd, Akt kinase, calcium/calmodulin-dependent protein kinase IV, mitogen-activated protein kinase kinase (MEKK-1), focal adhesion kinase (FAK), protein phosphatase (PP)2A, calcineurin... 

Govindarajan G, EbleDM, Lucchesi PA, Samarel AM 2000 Focal adhesion kinase is involved in angiotensin Il-mediated protein synthesis in cultured vascular smooth muscle cells. Circ Res... 

Wang, F., Nobes, C.D., HaU, A. and Spiegel, S., 1997, Sphingosine 1-phosphate stimulates Rho-mediated tyrosine phosphorylation of focal adhesion kinase and paxiUin in Swiss 3T5 fibroblasts. Biochem. J. 324 481-488. 

Tamura, M., Gu, J., Danen, E.H., Takino, T., Miyamoto, S., Yamada, KM., 1999, PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatidyhnositol 3-kinase/Akt cell survival pathway. JBiol Chem 274 ... 

Ilic D, Almeida EAC, Shlaepfer DD, Dazin P, Aizawa S, Damsky CH (1998) Extracellular matrix survival signals transduced by focal adhesion kinase suppress p53-mediated apoptosis.) Cell Biol 143 547-560... 

Cytoskeleton deregulation gelsolin, focal adhesion kinase (FAK), p21-activated kinase (PAK)... 

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)). 

Inactivation of the enzyme involved in cell adhesion (focal adhesion kinase) allows the cell to separate from the extracellular matrix. Changes to the cell surface, resulting in phosphatidyl serine externals a tion on the plasma membrane and external accumulation of sterols, allow the apoptotic cell to be recognized and eventually removed by phagocytosis. 

Chikumi, H., Fukuhara, S., and Gutkind, J. S. (2002). Regulation of G protein-linked guanine nucleotide exchange factors for Rho, PDZ-RhoGEF, and LARG by tyrosine phosphorylation Evidence of a role for focal adhesion kinase. /. Biol. Chem. 277, 12463-12473. 

Holinstat, M., Knezevic, N., Broman, M., Samarel, A. M., Malik, A. B., and Mehta, D. (2006). Suppression of RhoA activity by focal adhesion kinase-induced activation of pl90RhoGAP Role in regulation of endothelial permeability. J. Biol. Chem. 281, 2296-2305. 

Recendy, it has been shown that a-actinin is phosphorylated by focal adhesion kinase (FAK) and that this phosphorylation reduces the ability of a-actinin to bind actin (Izaguirre et al., 2001). The site of tyrosine phosphorylation is N-terminal to the first CH domain in a region that is most conserved between spectrin family proteins. 

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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