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doi: 10.1242/10.1242/jcs.00071

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Get a ligand, get a life: integrins, signaling and cell survival

Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Rd, La Jolla, CA, 92037, USA

View larger version (56K): [in a new window]   Fig. 1. Common signaling pathways initiated by ECM-ligated integrins. Integrin signaling is dependent upon the non-receptor tyrosine kinase activities of the FAK and src proteins as well as the adaptor protein functions of FAK src and Shc to initiate downstream signaling events. Common kinase signaling cascades are illustrated, but for clarity cooperativity or cross-activation between different cascades has been omitted. One caveat to the interpretation of the role of integrins in mediating survival, as discussed here, is that kinase effects are often studied through the use of constitutively active constructs. It is not clear whether this approach precisely mimics integrin-mediated signaling pathways, as shown here. Also absent are the host of cytoskeletal proteins, including -actinin, actin, vinculin, talin and paxcillin, that function as adaptors, recruiters and scaffolds on which these signaling events occur.

View larger version (71K): [in a new window]   Fig. 2. Integrin-mediated resistance to stress-induced apoptosis via the Ras-PI-3-kinase-Akt pathway. Cell stresses such as serum withdrawal result in the localization of proapoptotic Bcl-2 family proteins, such as Bad (or Bod or Bax), at the mitochondria, which results in cytochrome C leakage and Apaf-1-mediated assembly of the caspase-9-containing apoptosome complex. Ras-mediated activation of PI 3-kinase triggers the phosphorylation of Akt through the functions of phosphoinositide-dependent kinases (PDKs), such as PDK1, PDK2 and ILK. Akt then acts as a central regulator of cell survival, phosphorylating mTOR (and E4BP, allowing iEF-4E activation of CAP-dependent translation; not shown), while also phosphorylating the proapoptotic protein Bad, leading to displacement from the mitochondria and sequestration by chaperones of the 14-3-3 family. Akt also potentiates the transactivating potential of NFkB, leading to the increased expression of NFkB target genes, including Bcl-2 and Bcl-xl., Akt signaling is attenuated by the action of phosphatases such as PTEN.

View larger version (89K): [in a new window]   Fig. 3. Roles for ERK activation in resistance to stress-induced apoptosis. Concomitantly with the activation of the Akt pathway (see Fig. 1), integrin ligation leads to the activation of the Ras-Raf-MEK-ERK cascade. Activated Ras recruits Raf, which binds to and activates MEK, and subsequently ERK, which are all bound on a ksr scaffold. The phosphorylation of Bcl-2 by Erk on Thr 56, Thr 74 or Ser 84 prevents its recognition by ubiquitin ligases, whereas phosphorylation at Ser 70 has been reported to both increase and decrease the prosurvival character of Bcl-2. Of the ksr-bound proteins, both Raf and Mek (as well as the Erk-substrate, Rsk, not shown) are capable of phosphorylating the proapoptotic protein Bad (indicated by the green circling arrow, starred), leading to its displacement from the mitochondria and subsequent sequestration by 14-3-3 proteins.

View larger version (79K): [in a new window]   Fig. 4. Mechanisms for integrins to influence DR-mediated apoptosis. The induction of apoptosis by DRs is triggered by ligand-induced clustering, leading to the recruitment of FADD and subsequently initiator caspases such as caspase 8 or 10 via their DED domains (banana shape) to form a DISC (death-inducing signal complex). Caspases autoactivate and form dimers, leaving the DED domains at the DISC, and go on to cleave downstream targets, such as Bid (which will activate the intrinsic apoptosis pathway) and the executioner caspases. The formation of the DISC is influenced by both the presence of DED-containing inhibitory proteins, such as FLIPs, and protein kinase C activity. Activated PKC blocks recruitment and/or activation of caspase 8 at the DISC and is permissive for the assembly of signaling downstream of cFLIP via the Raf-MEK-ERK pathway or through Traf to JNK (not shown). Integrin ligation leads to signaling via the ERK pathway (as described in Fig. 3) as well as to NFB translocation to the nucleus, which together promote the transcription of anti-apoptotic proteins such as the IAPs and cFLIP. Erk activation of Rsk also leads to phosphorylation of the transcription factor CEBP, creating an XEXD motif that blocks caspase 8 activity.