f extracellular agonists promote the 'outside-in' arm of the pathway, whereas the 'inside-out' arm is promoted by ligands binding the cytoplasmic tail of beta-integrin receptors, prompting their activation. Talin and kindlin play essential roles in beta integrin activation, with talin binding proposed to provide the final step. In a model for the mechanism of talin-mediated activation, Rap1 activation downstream of many upstream activating pathways leads to the interaction of Rap1 with its effector Apbb1ip (Riam). Rap1 is a RAS-like member of the small monomeric G protein superfamily, and one important activator of its signaling is protein kinase C (PKC). Apbb1ip plays a central role in the recruitment of talins to the membrane. The two vertebrate talin genes have distinct but overlapping functions. The N-terminal talin head is an atypical FERM domain with an F0 domain in addition to the three F1, F2 and F3 domains. The F3 domain binds to the NPxY motif in beta-integrin tails. The talin head is linked to the talin rod by a large and unstructured region. The rod is composed of 62 alpha helices that form 13 4- or 5-helix bundles. The rod domain contains multiple protein binding sites, including a second integrin-binding site and several for Apbb1ip. In addition to talins, kindlins (Fermt) also bind to the tail of beta integrin receptors and regulate their function. There are three kindlins (Fermt1, 2 and 3) in mammals; like talins, they are FERM-containing proteins, bind the NPxY motif of beta integrins to activate them and may function as co-activators. While talins and kindlins activate integrins, binding of proteins such as Itgb1bp1 (Icap1) or filamin (alpha/beta) inhibit the receptors by interfering with the binding of talin and/or kindlin. The interaction of Fblim1 (migfilin) with filamin, or of Krit1 with Itgb1bp1, prevents the binding of these inhibitors to integrins. Others, such as Sharpin and Fab3 (known as MDGI), inhibit beta integrins by binding to the alpha subunits. The molecular mechanisms of kindlin-mediated activation are not well understood. Integrin clustering and formation of multiprotein complexes with Ilk (Integrin linked kinase) and Ptk2, known as focal adhesion kinase (Fak), are important elements of 'outside-in' signaling. Ilk binds the cytoplasmic tail of beta integrin and mediates several protein-protein interactions. The C-terminal domain is involved in the interaction with integrin, parvin(s) and paxilin, the middle domain binds PIP2, necessary for activation, the N-terminal ankyrin repeats (ANK) are crucial for the interaction with Lims 1/2, (LIM) domain-containing proteins also known as Pinch1/2. Lims1 interacts with Nck2, a major effector of receptor tyrosine kinases (RTKs). The kinase activity of Ilk is highly controversial and Ilk is considered a pseudokinase. However, Ilk phosphorylation has been documented in vitro with Gsk3b, Akt and others as substrates. Ilk is negatively regulated by Ilkap or Pten phosphatases. The multiple domains of Ptk2 underlie the interaction with talin and paxilin and other proteins, leading to integration of multiple signaling cascades. Via ECM organization and protein clustering, integrins synergize with growth factors to integrate downstream signaling cascades. Integrin mediated signaling plays important roles in many cellular processes - from cell migration, adhesion and ECM assembly to cell differentiation and proliferation, survival and motility. Alterations in the integrin pathway have been implicated in a number of human diseases. Mutations in several members of integrin, kindlin and filamin families are reported. Loss-of-function mutations in the inhibitor antagonist KRIT1 are found in 40% of patients with autosomal cerebral cavernous malformation. To see the ontology report for annotations, GViewer and download, click here.
[Click to see the ontology report for associated GO term - GO:0007229, related KEGG map - map04510 and entry at Reactome - REACT_13552.1]...(less)