Focal adhesion complexes

FAT Focal adhesion targeting domain Binding to focal adhesions complexes... 

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. 

Despite this complexity, most integrins share two, key interrelated functions first, to promote the assembly and organization of the actin cytoskeleton [122, 123] and second, to regulate signal transduction cascades [124-126], Spanning the cell membrane, these subunits serve as a communication pathway, linking the actin cytoskeleton and intracellular cytoplasmic proteins involved in focal adhesion complexes (FACs) with the cell s dynamic extracellular environment (Fig. 8) [127-130]. There are at least 50 distinct proteins known to be involved in FACs. Actin [131], vinculin, talin, tensin, a-actinin, and filamin provide a structural role, while focal adhesion kinase [132], integrin-linked kinase, Src-family kinase, PINCH, paxillin... 

ECM, cytoplasmic proteins, and the actin cytoskeleton in formation of a focal adhesion complex... 

The structural integrity of microfilaments has been shown to be necessary for signal transduction within osteoblasts. Examination of the effects of mechanical strain on the expression of major structural elements of the cytoskeleton indicated that the amount of tubulin decreased by 75% and the amount of vinculin, a major component of focal adhesion complexes, increased by about 250%. Immunofluorescence microscopy demonstrated that mechanical strain led to increased formation and thickening of actin stress fibers, with dissociation of the microtubules and a clear increase in levels of vinculin at the peripheral edges of the cell. This suggests that mechanical strain leads to a coordinated change in both the cytoskeleton and in ECM proteins that facilitate tighter adhesion of osteoblasts and their ECM. 

A specialized cell-matrix contact point, which is stracturaUy distinct from focal adhesion complexes. See Linder, S. and Aepfelbacher, M., Podo-somes adhesion hot-spots of invasive cells. Trends Cell Biol. 13, 376-385, 2003 McNiver, M.A., Baldassarre, M., and Buccione, R., The role of dynamin in the assembly and function of podosomes and invadopodia. Front. Biosci. 9, 1944-1953, 2004 Linder, S., and Kopp, R, Podosomes at a glance, J. Cell Sci. 118, 2079-2082, 2005. 

A tempting model has been proposed that, upon recruitment to focal adhesion complexes, FAK undergoes conformational change and interacts through its amino terminal domain with the integrin cytoplasmic tail (43-45). The amino terminal domain of... 

The subcellular localization of protein tyrosine phosphatases is an important aspect of their function. The sequences of cytoplasmic protein tyrosine phosphatases frequently demonstrate sequence signals specifying a particular subcellular localization. This ensures that protein tyrosine phosphatases are only active at defined subcellular sites. Specifically, localization to focal adhesion complexes mediated by proline-rich sequences has been observed for some PTPs. The presence of SH2 domains in cytoplasmic protein tyrosine phosphatases also shows that these are coupled, via... 

Besides regulatory effects on signalling through cellular cytokine and growth factor receptors, adhesion processes are controlled by the individual /V-glycan content of particular adhesion molecules. A critical step in cellular invasiveness is the fine-tuned regulation of cell adhesion to the extracellular matrix, executed by focal cell adhesion synapses (focal adhesion complexes) that are regulated by the focal adhesion kinase... 

Integrins encompass but one of the families of mechanosensors, but the signals they transmit through focal adhesion complexes are critical for cell phenotype. Other classes transmit signals specific to cell-cell communication and inflammation, and all of the adhesion molecules work in tandem in the valve endothelium to determine the fate of the cell and the entire tissue. 

Mackay, D.J., Esch, E., Eurthmayr, H., Hall, A. Rho- and rac-dependent assembly of focal adhesion complexes and actin filaments in penneabUized fibroblasts an essential role for ezrin/radixin/moesin proteins. J. CeU Biol. 138, 927-938 (1997)... 

FIGURE 34.1 Illustration of a focal adhesion complex. A cluster of transmembrane integrin receptor heterodimers is shown interacting with extracellular matrix proteins and cytoplasmic proteins vinculin, a-actinin, talin, and focal adhesion kinase (FAK). This complex interacts with the actin cytoskeleton. Adapted horn Petit, V. and Thiery, J.-P., Biol. Cell. 92, 477, 2000. With permission Yamada, K.M. and Miyamoto, S., Curr. Opin. Cell BioL 7, 681, 1995. With permission. 

Westendorf et al, 2004, Giancotti and Ruoslahti, 1999). FAK is one of the main components of the integrin mechanotransduction pathway (Rubin et al, 2006, Shakibaei et al., 2008). Once associated with the focal adhesion complex (FAC), FAK is subsequently activated, autophosphorylates and then binds with sarcoma (Src) to form a Src-homology-2 binding domain (Millward-Sadler and Salter, 2004, Yoon and Fisher, 2007). As an SFIC-2 it is able to phosphorylate other proteins such as paxillin and tensin (Millward-Sadler and Salter, 2004, Giancotti and Ruoslahti, 1999). 

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