A Role for Ubiquitin Binding in Bcr-Abl Transformation
Final rept. 1 Jun 2007-31 May 2009
UNIVERSITY OF MEDICINE AND DENTISTRY OF NEW JERSEY NEWARK
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We have previously identified a docking site for ubiquitin in the amino-terminus of p210 BCRABL. In this proposal we have examined whether this association has implications for BCRABL signaling and transforming activity. Our approach was to map the binding site for ubiquitin in BCRABL and generate a binding mutant. The binding site is immediately adjacent to the GRB2 binding site, but the two binding activities are genetically separable. Although ubiquitin binding does not regulate BCRABL tyrosine kinase activity, the mutant can no longer interact with phosphorylated beta-catenin suggesting that BCRABL interacts with beta-catenin in a ubiquitin-dependent manner. A BCRABL mutant that cannot bind ubiquitin, but can still interact with Grb2, was tested for transforming activity in murine myeloid cells. The mutant can still support IL-3 independent growth in these cells indicating that some, but not all BCRABL activities are dependent upon this association.
- Medicine and Medical Research