242 The Effect of Conformation On Function in Grb7, An Intracellular Signaling Protein Essential in Inflammatory Arthritis, Cancer, and Bone Resorption

Thursday, November 5, 2009: 11:20 AM
Hereford (Camino Real Hotel)
Barbara A. Lyons , Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM
Dennis Johnson , Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM
Sally Pias , Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM
Tabitha Peterson , Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM
Renee Benallie , Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM
The synergistic relationship between chronic inflammation and cancer is now widely recognized and accepted. Though Grb7 is considered a cell migration signaling protein in cancer progression, it is also implicated in several inflammatory processes. We have shown that Grb7 binds through an intracellular mechanism with FHL2, a potent inhibitor of osteoclast maturation and down-regulator of inflammatory arthritis bone resorption. By this mechanism, over-expression of Grb7 may decrease the effectiveness of FHL2 and promote the resorption of bone. Through NMR chemical shift analyses, and isothermal titration calorimetry, we have shown the central RA-PH domains of Grb7 are involved in an intra-molecular interaction with the Grb7 C-terminal SH2 domain. The dimerization state of Grb7 may contribute to Grb7 RA-PH domain availability for binding to FHL2, and further, the dimerization state of Grb7 appears controlled by the Grb7-SH2 domain phosphorylation state. We propose a self-regulatory Grb7 mechanism modulated by dimerization state, whereby dimerization state is selected via a tyrosine phosphorylation switch.