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Integrin Cytoplasmic Domains and Ligand Affinity Modulation

Institution: Scripps Research Institute
Investigator(s): Timothy O'Toole, Ph.D.
Award Cycle: 1994 (Cycle 3) Grant #: 3RT-0320 Award: $522,649
Subject Area: Cardiovascular Disease
Award Type: Research Project Awards

Initial Award Abstract
As is well-documented, excessive tobacco use results in multiple health problems. Some of the most severe are trauma such as heart attack or stroke, which result from unregulated platelet aggregation at sites of tobacco-induced damage to blood vessels. An understanding of platelet function and the cellular mechanisms underlying aggregation are therefore crucial in designing antithrombotic therapies.

Platelet aggregation is mediated by a protein on its cell surface, the integrin àIIb 3. An important property Of àIIb 3 is that its adhesiveness can be regulated. Specifically, in resting platelets, àIIb 3 is incapable of binding the blood protein fibrinogen (Fg). In response to vascular injury, however, àIIb 3 is "activated," becoming a competent Fg receptor, and initiating clot formation and aggregation. While the mechanisms of this activation remain obscure, it is generally believed that platelet signals interact with the intracellular tails of àIIb 3, are transduced across the cell membrane, and effect a change in integrin adhesive properties. It is the goal of this proposal to identify these signals and the specific sites within the àIIb 3 tails that are involved.

Studies throughout the course of this proposal have delineated several important properties of àIIb 3 activation. First, the activation of this integrin is an energy dependent and cell type-specific process that involves sequences in both the àIIb and 3 tails. Second, through extensive mutagenesis efforts we have mapped important tail residues. They include membrane proximal residues in both à and subunits and a distal NPXY motif in the 3 tail. Third, we have shown that by independent overexpression of the 3 tail itself, we can alter integrin adhesive properties. Finally, we have isolated a novel, intracellular protein which specifically interacts with the 3 tail, whose function is as yet unknown. In sum, our results are consistent with a model suggesting the existence of intracellular regulatory proteins affecting àIIb 3 binding properties or affinity state. These studies are important in that they might suggest novel targets for intervention in trauma resulting from abnormal or unregulated platelet aggregation.

Distinct functions of integrin alpha and beta subunit cytoplasmic domains in cell spreading and formation of focal adhesions
Periodical: Journal of Cell Biology Index Medicus:
Authors: Ylanne J, Chen Y, O'Toole TE, Loftus JC, Takada Y, Ginsberg MH ART
Yr: 1993 Vol: 122 Nbr: 1 Abs: Pg: 223-233

Integrin cytoplasmic domains mediate inside-out signal transduction
Periodical: Journal of Cell Biology Index Medicus:
Authors: O'Toole TE, Katagiri Y, Faull R, et al ART
Yr: 1994 Vol: 124 Nbr: 6 Abs: Pg: 1047-1059

"Inside-out" signal transduction inhibited by isolated integrin cytoplasmic domains
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: Chen Y-P, O'Toole TE, Shipley T, et al ART
Yr: 1994 Vol: 269 Nbr: 28 Abs: Pg: 18307-18310

Regulation of integrin function and cellular adhesion
Periodical: Stem Cells Index Medicus:
Authors: Stuiver I, O'Toole TE ART
Yr: 1995 Vol: 13 Nbr: 3 Abs: Pg: 250-262

Regulation of integrin affinity states through an NPXY motif in the beta subunit cytoplasmic domain
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: O'Toole TE, Ylanne J, Culley BC ART
Yr: 1995 Vol: 270 Nbr: 15 Abs: Pg: 8553-8558

A conserved membrane-proximal region of an integrin cytoplasmic domain specifies ligand binding afinity
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: Hughes PE, O'Toole TE, Ylanne J, Shattil SJ, Ginsberg MH ART
Yr: 1995 Vol: 270 Nbr: 21 Abs: Pg: 12411-12417

A point mutation in the integrin beta 3 cytoplasmic domain (S752P) impairs bidirectional signaling through alpha II beta 3 (platelet glycoprotein II-b-IIIa).
Periodical: Blood Index Medicus:
Authors: Chen YP, O'Toole TE, Rosa JP, Ginsberg MH ART
Yr: 1994 Vol: 84 Nbr: Abs: Pg: 1857-1865

Modulation of cell adhesion by changes in alpha L beta 2 (LFA-1,CD11a/CD18) cytoplasmic domain/cytoskeletal interaction
Periodical: Journal of Experimental Medicine Index Medicus:
Authors: Peter K, O'Toole TE ART
Yr: 1995 Vol: 181 Nbr: Abs: Pg: 315-326

Mutation of the cytoplasmic domain of the integrinbeta 3 subunit: differential effects on cell spreading, recruitment to adhesion plaques, endocytosis and phagocytosis
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: Ylanne J, Huuskonen J, O'Toole TE, Ginsberg MH, Virtanen I, Gahmberg CG ART
Yr: 1995 Vol: 270 Nbr: Abs: Pg: 9550-9557

Beta 3-endonexin, a novel polypeptide that interacts specifically with the cytoplasmictail of the integrin beta 3 subunit
Periodical: Journal of Cell Biology Index Medicus:
Authors: Shattil SJ, O'Toole TE, Eigenthaler M, Thon V, Williams M, Babior BM, Ginsberg MH ART
Yr: 1995 Vol: 131 Nbr: Abs: Pg: 807-816