Integrin Signaling


Pathway Description

Integrins are cell surface glycoproteins that are involved in cell-cell and cell-extracellular matrix (ECM) interactions. These interactions are the basis for a number of diverse effects that include cell migration and anchorage, cell growth and differentiation. Integrins are a family of more than 20 different cell surface receptors which are comprised of non covalently associated α and β subunits. The ligands for integrins include the ECM proteins vitronectin, fibronectin and collagen.Integrins have the property of attaching the cell to the ECM and the cytoskeleton to the cell membrane. In doing so, integrins are able to communicate changes in the external environment of the cell and translate them into structural changes within the cell. It is the cytoplasmic face of the Integrin β subunit that is responsible for interactions with cytoskeletal proteins like a actinin, talin, vinculin, zyxin and F-actin. Other key mediators of integrin signaling include Focal adhesion kinase (FAK) and integrin linked kinase (ILK). These proteins are important in the formation of focal adhesions, which are responsible for signal transduction and assembly of stress fibers.

Cytoskeletal remodeling is important in many cellular responses, including cell adhesion, spreading, and motility. Rho family members of small guanosine triphosphatases (GTPases)--RHO, RAC, and CDC42--have been implicated as critical regulators of cytoskeletal changes.The primary changes in cytoskeleton are brought about by interaction between actin and myosin. Myosin light chain kinase (MLCK) is the enzyme that phosphorylates and activates myosin light chain (MLC). MLCK is inhibited by p21 activated kinase (PAK) an effector molecule activated by RAC and CDC42. The inhibition of MLCK thus regulates cytoskeletal rearrangement. On the other hand, Rho-kinase (ROCK) an effector molecule of RHO phosphorylates myosin light chain phosphatase (MLCP) and inhibits the phosphatase activity. The inhibition of MLCP increases phosphorylation and activation of MLC, which then mediates the assembly of stress fibers and other cytoskeletal changes.

Integrins also trigger the activation of mitogen activated protein kinase (MAPK) pathways. Integrin mediated activation of PAK leads to the phosphorylation and activation of MAPK kinase MEK1. The activation of MEK1 leads to the downstream activation of Extracellular signal regulated kinase (ERK) which in turn activates MLCK promoting stress fiber formation. PAK is also involved in the activation of the MAPK c Jun kinase (JNK). In addition to PAK, another integrin activated kinase, FAK triggers the adapter protein SHC and signaling through the RAS/MAPK pathway leading to cell proliferation. Likewise, the Integrin mediated triggering of ILK leads to activation of a LIM domain containing protein PINCH which in turn activates a SH2/SH3 domain containing protein non-catalytic region of tyrosine kinase adaptor protein 2 (NCK2). NCK2 interacts with several growth factor pathways in addition to interacting with cytoskeletal proteins. Thus there are several integrin activated kinases that could serve as sites of convergence in the action of integrins and growth factors.

This pathway highlights the important components of integrin signaling.