The primary goal of this renewal proposal is to determine the mechanism and consequences of intracellular signals from the integrin a1b1. Upon ligand binding, this receptor produces multiple signals which organize the actin cytoskeleton and stimulant cell growth. Previous studies have shown that swapping the cytoplasmic domains of a1 and beta1 leads to an integrin with defective signaling despite its capacity to bind ligand. An insertion within the cytoplasmic domain of the beta subunit can restore the signaling properties of this receptor. This model will be used to study the mechanism of the transmembrane conformation change occurring upon signaling.
The second aim will compare wild type and defective receptors to dissect the proximal aspects of signaling via FAK. In the defective receptor FAK is activated yet the chimeric receptor does not phosphorylate CAS. Studies will focus upon cSrc and its ability to mediate the signaling between FAK and CAS. Mutant forms of cSrc will be expressed to determine if they will rescue the defective receptors.
The third aim will focus on a1b1 growth signals through the adaptor Shc. Studies in Jurkat cells found that the receptor tyrosine phosphatase CD45 and the Src kinase Lck are required and the Src kinase Fyn is not sufficient in the these cells, in contrast to fibroblasts. Studies will address the mechanism of Src activation and Shc signaling. Finally, studies will address the consequences of the above mentioned growth signals using the two collagen receptors a1b1 and a2b1, which differ in their ability to phosphorylate Shc. This system will be use to examine the nature of integrin signals involved in the synergy with peptide growth factor receptor signals.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Pathobiochemistry Study Section (PBC)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Columbia University (N.Y.)
Schools of Medicine
New York
United States
Zip Code
Palazzo, Alexander F; Eng, Christina H; Schlaepfer, David D et al. (2004) Localized stabilization of microtubules by integrin- and FAK-facilitated Rho signaling. Science 303:836-9
Niu, Shi; Xie, Haichun; Marcantonio, Eugene E (2003) Integrin-mediated tyrosine phosphorylation of Shc in T cells is regulated by protein kinase C-dependent phosphorylations of Lck. Mol Biol Cell 14:349-60
Smilenov, L B; Mikhailov, A; Pelham, R J et al. (1999) Focal adhesion motility revealed in stationary fibroblasts. Science 286:1172-4
David, F S; Zage, P E; Marcantonio, E E (1999) Integrins interact with focal adhesions through multiple distinct pathways. J Cell Physiol 181:74-82
Zage, P E; Marcantonio, E E (1998) The membrane proximal region of the integrin beta cytoplasmic domain can mediate oligomerization. Cell Adhes Commun 5:335-47
Kern, A; Marcantonio, E E (1998) Role of the I-domain in collagen binding specificity and activation of the integrins alpha1beta1 and alpha2beta1. J Cell Physiol 176:634-41
Marcantonio, E E; David, F S (1997) Integrin receptor signaling: the propagation of an alpha-helix model. Matrix Biol 16:179-84
Wary, K K; Mainiero, F; Isakoff, S J et al. (1996) The adaptor protein Shc couples a class of integrins to the control of cell cycle progression. Cell 87:733-43
Hendey, B; Lawson, M; Marcantonio, E E et al. (1996) Intracellular calcium and calcineurin regulate neutrophil motility on vitronectin through a receptor identified by antibodies to integrins alphav and beta3. Blood 87:2038-48
Briesewitz, R; Kern, A; Smilenov, L B et al. (1996) The membrane-cytoplasm interface of integrin alpha subunits is critical for receptor latency. Mol Biol Cell 7:1499-509

Showing the most recent 10 out of 16 publications