QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online December 31, 2008
doi: 10.1242/10.1242/jcs.041624

This Article Summary Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Legate, K. R. Articles by Fässler, R. Search for Related Content PubMed Articles by Legate, K. R. Articles by Fässler, R. Social Bookmarking                         What's this?

Mechanisms that regulate adaptor binding to β-integrin cytoplasmic tails

Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany

View larger version (84K): [in this window] [in a new window]   Fig. 1. Alignment of β-integrin-tail sequences. β-integrin tails from several species were aligned manually. The divergent sequences of human β4 integrin and β8 integrin were not included. Residues that are normally buried in the membrane but that might become available for adaptor binding upon integrin activation are depicted in green. The conserved NxxY motifs and HDR[R/K] motif are highlighted in bold. Residues that might be phosphorylated to regulate adaptor binding are highlighted in red. Residues are numbered according to the National Center for Biotechnology Information (NCBI) sequence.

View larger version (15K): [in this window] [in a new window]   Fig. 2. Adaptor-binding sites along the β3-integrin tail. The mapped positions of adaptors that have been shown to bind to the β3-integrin cytoplasmic tail are indicated by solid lines. Positions of adaptors that have binding sites on other integrins and are discussed in the text, but that have not been shown to bind to β3 integrin, are indicated by broken lines. Residues that are normally buried in the membrane are colored green. Residues that can be phosphorylated by various kinases (see text) are highlighted in red.

View larger version (86K): [in this window] [in a new window]   Fig. 3. Proposed mechanisms by which adaptor binding to β integrins is regulated. (A) A phosphotyrosine switch between the binding of talin and tensin to β3 integrin. (Left) A structural scaffold. In the unphosphorylated state, the NPLY motif of β3 integrin binds to the PTB domain of talin. Connections to the actin cytoskeleton occur through direct interactions between talin and actin, as well as through interactions with vinculin. (Right) A signaling scaffold. Phosphorylation (red star) of the NPLY tyrosine residue displaces talin and allows tensin to bind to the β3-integrin tail. Interactions of the adaptor proteins with actin are retained and reinforced, but intracellular signaling can now occur through the production of PtdIns(4,5)P2 by talin-bound PIPKI and by the activation of Akt by tensin-bound PDK1. (B) A phosphothreonine switch between the binding of filamin and 14-3-3 to β2 integrin. (Left) Filamin interacts with the serine/threonine-rich intervening sequence when it is unphosphorylated, mostly via hydrophobic interactions. Connections to the actin cytoskeleton occur through the actin-binding domains of the filamin dimer. The filamin-integrin interaction inhibits cell migration and impairs integrin activation in some cell types. (Right) Phosphorylation (red star) of T758 in β2 integrin displaces filamin and allows binding of the adaptor protein 14-3-3, primarily through interactions with the phosphate group of phosphothreonine. The 14-3-3–integrin interaction stimulates cell spreading and migration by promoting actin-cytoskeleton rearrangement in a Rac1- and Cdc42-dependent manner. The steps that lead from 14-3-3 binding to GTPase activation are unknown. Both filamin and 14-3-3 function as dimers, so they might aid integrin clustering by binding to two integrins simultaneously. (C) Co-adaptor-mediated binding of ILK to β integrin. The IPP complex, consisting of ILK, PINCH and parvin, assembles first in the cytosol, and is recruited to integrin tails in a paxillin- and kindlin-2-dependent manner. The details of how the IPP complex is recruited to integrins, and the precise roles of paxillin and kindlin 2 in the process, are unknown. Once the IPP complex is integrated into a focal adhesion, it has both structural and signaling roles. Adhesion strengthening can occur through binding of F-actin to parvin isoforms; crosstalk with receptor tyrosine kinases (RTK) is possible via a PINCH-Nck2 interaction; and ILK participates in signaling by facilitating the phosphorylation (P) of the kinases Akt (PKB) and GSK3β. Molecules are not drawn to scale.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

Twitter