August 6th, 2009

Kolltan Founder, Board Member and Chairman of Scientific Advisory Board Publishes Article on Receptor Tyrosine Kinase Signaling

Kolltan Pharmaceuticals, Inc. announced today that Dr. Joseph Schlessinger, Kolltan's founder, member of its Board of Directors and Chairman of its Scientific Advisory Board, has published an article in Cell on receptor tyrosine kinase signaling. The research described in the article was performed in the laboratory of Dr. Schlessinger at the Yale School of Medicine. A summary of the article and link to the full article follow.

The Selectivity of Receptor Tyrosine Kinase Signaling Is Controlled by a Secondary SH2 Domain Binding Site
Jae Hyun Bae, Erin Denise Lew, Satoru Yuzawa, Francisco Tome, Irit Lax, and Joseph Schlessinger,
Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA

Summary

SH2 domain-mediated interactions represent a crucial step in transmembrane signaling by receptor
tyrosine kinases. SH2 domains recognize phosphotyrosine (pY) in the context of particular sequence
motifs in receptor phosphorylation sites. However, the modest binding affinity of SH2 domains to pY
containing peptides may not account for and likely represents an oversimplified mechanism for regulation
of selectivity of signaling pathways in living cells. Here we describe the crystal structure of the activated
tyrosine kinase domain of FGFR1 in complex with a phospholipase Cg fragment. The structural
and biochemical data and experiments with cultured cells show that the selectivity of phospholipase Cg
binding and signaling via activated FGFR1 are determined by interactions between a secondary binding
site on an SH2 domain and a region in FGFR1 kinase domain in a phosphorylation independent manner.
These experiments reveal a mechanism for how SH2 domain selectivity is regulated in vivo to mediate
a specific cellular process.

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