Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Genes & Dev. 20 (8): 927-932

Copyright © 2006 by Cold Spring Harbor Laboratory Press.


RESEARCH COMMUNICATION

In vivo beta1 integrin function requires phosphorylation-independent regulation by cytoplasmic tyrosines

Hong Chen1, Zhiying Zou1, Kendra L. Sarratt2, Diane Zhou1, MaoZhen Zhang1, Eric Sebzda1, Daniel A. Hammer2, and Mark L. Kahn1,3

1 Department of Medicine
2 Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

Abstract: Integrins are heterodimeric adhesion receptors associated with bidirectional signaling. In vitro studies support a role for the binding of evolutionarily conserved tyrosine motifs (NPxY) in the beta integrin cytoplasmic tail to phosphotyrosine-binding (PTB) domain-containing proteins, an interaction proposed to be dynamically regulated by tyrosine phosphorylation. Here we show that replacement of both beta1 integrin cytoplasmic tyrosines with alanines, resulting in the loss of all PTB domain interaction, causes complete loss of beta1 integrin function in vivo. In contrast, replacement of beta1 integrin cytoplasmic tyrosines with phenylalanines, a mutation that prevents tyrosine phosphorylation, conserves in vivo integrin function. These results have important implications for the molecular mechanism and regulation of integrin function.

Key Words: Integrin • tyrosine phosphorylation • phospho-tyrosine-binding domain • inside-out signaling • outside-in signaling • conditional knock-in

Received for publication January 9, 2006. Accepted for publication February 17, 2006.


3 Corresponding author.

E-MAIL markkahn{at}mail.med.upenn.edu; FAX (215) 573-2094.

Supplemental material is available at http://www.genesdev.org.

Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1408306


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Fibronectin mediates mesendodermal cell fate decisions.
P. Cheng, P. Andersen, D. Hassel, B. L. Kaynak, P. Limphong, L. Juergensen, C. Kwon, and D. Srivastava (2013)
Development 140, 2587-2596
   Abstract »    Full Text »    PDF »
{beta}1 Integrin NPXY Motifs Regulate Kidney Collecting-Duct Development and Maintenance by Induced-Fit Interactions with Cytosolic Proteins.
S. Mathew, Z. Lu, R. J. Palamuttam, G. Mernaugh, A. Hadziselimovic, J. Chen, N. Bulus, L. S. Gewin, M. Voehler, A. Meves, et al. (2012)
Mol. Cell. Biol. 32, 4080-4091
   Abstract »    Full Text »    PDF »
{beta}1 integrin cytoplasmic tyrosines promote skin tumorigenesis independent of their phosphorylation.
A. Meves, T. Geiger, S. Zanivan, J. DiGiovanni, M. Mann, and R. Fassler (2011)
PNAS 108, 15213-15218
   Abstract »    Full Text »    PDF »
{beta} Integrin Tyrosine Phosphorylation Is a Conserved Mechanism for Regulating Talin-induced Integrin Activation.
N. J. Anthis, J. R. Haling, C. L. Oxley, M. Memo, K. L. Wegener, C. J. Lim, M. H. Ginsberg, and I. D. Campbell (2009)
J. Biol. Chem. 284, 36700-36710
   Abstract »    Full Text »    PDF »
Negative regulation of activated {alpha}2 integrins during thrombopoiesis.
Z. Zou, A. A. Schmaier, L. Cheng, P. Mericko, S. K. Dickeson, T. P. Stricker, S. A. Santoro, and M. L. Kahn (2009)
Blood 113, 6428-6439
   Abstract »    Full Text »    PDF »
The mechanical integrin cycle.
E. Puklin-Faucher and M. P. Sheetz (2009)
J. Cell Sci. 122, 179-186
   Abstract »    Full Text »    PDF »
Mechanisms that regulate adaptor binding to {beta}-integrin cytoplasmic tails.
K. R. Legate and R. Fassler (2009)
J. Cell Sci. 122, 187-198
   Abstract »    Full Text »    PDF »
The N-terminal Domains of Talin Cooperate with the Phosphotyrosine Binding-like Domain to Activate {beta}1 and {beta}3 Integrins.
M. Bouaouina, Y. Lad, and D. A. Calderwood (2008)
J. Biol. Chem. 283, 6118-6125
   Abstract »    Full Text »    PDF »
Talin is required for integrin-mediated platelet function in hemostasis and thrombosis.
B. G. Petrich, P. Marchese, Z. M. Ruggeri, S. Spiess, R. A.M. Weichert, F. Ye, R. Tiedt, R. C. Skoda, S. J. Monkley, D. R. Critchley, et al. (2007)
J. Exp. Med. 204, 3103-3111
   Abstract »    Full Text »    PDF »
Loss of talin1 in platelets abrogates integrin activation, platelet aggregation, and thrombus formation in vitro and in vivo.
B. Nieswandt, M. Moser, I. Pleines, D. Varga-Szabo, S. Monkley, D. Critchley, and R. Fassler (2007)
J. Exp. Med. 204, 3113-3118
   Abstract »    Full Text »    PDF »
Structure-function analysis reveals discrete {beta}3 integrin inside-out and outside-in signaling pathways in platelets.
Z. Zou, H. Chen, A. A. Schmaier, R. O. Hynes, and M. L. Kahn (2007)
Blood 109, 3284-3290
   Abstract »    Full Text »    PDF »
Novel Platelet and Vascular Roles for Immunoreceptor Signaling.
F. F. Samaha and M. L. Kahn (2006)
Arterioscler Thromb Vasc Biol 26, 2588-2593
   Abstract »    Full Text »    PDF »
Screening for PTB Domain Binding Partners and Ligand Specificity Using Proteome-Derived NPXY Peptide Arrays.
M. J. Smith, W. R. Hardy, J. M. Murphy, N. Jones, and T. Pawson (2006)
Mol. Cell. Biol. 26, 8461-8474
   Abstract »    Full Text »    PDF »
Development requires activation but not phosphorylation of beta1 integrins..
Y. Pylayeva and F. G. Giancotti (2006)
Genes & Dev. 20, 1057-1060
   Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882