SH2-containing phosphotyrosine phosphatase SHP-1 is involved in BCR-ABL signal transduction pathways.

The BCR-ABL fusion protein is strongly implicated in the malignant process of Philadelphia (Ph-1)-positive leukemia. The BCR-ABL fusion protein exhibits a deregulated tyrosine kinase activity capable of phosphorylating different cellular substrates in vivo and in vitro. SHP-1 (SHPTP1, PTP1C, HCP, SHP) is an SH2 domain-containing tyrosine phosphatase expressed predominantly in hematopoietic cells. The association of the murine motheaten phenotype of severe hematopoietic dysregulation with loss of SHP-1 tyrosine phosphatase activity indicates a critical role of SHP-1 in the regulation of hematopoietic cell growth and differentiation. Experiments were performed to determine whether SHP-1 might form specific complexes with BCR-ABL signaling pathway. We found that SHP-1 was highly and constitutively tyrosine phosphorylated in 32DCl3 and TF-1 cells transfected with BCR-ABL expression vector. Furthermore, SHP-1 and BCR-ABL formed stable complexes in BCR-ABL expressing cells. Direct binding between SHP-1 and Grb2 was observed in vitro. Expression of BCR-ABL in TF-1 cells resulted in a two-fold increase in SHP-1 phosphatase activity. BCR-ABL tyrosine kinase was able to phosphorylate recombinant SHP-1 protein in vitro. SHP-1 therefore has the capacity to bind and potentially modulate the signaling effectors involved in activation of Ras, and accordingly, regulation of cellular transformation of BCR-ABL.