CRKL links p210(BCR/ABL) with paxillin in chronic myelogenous leukemia cells

R. Salgia, N. Uemura, K. Okuda, J. L. Li, E. Pisick, M. Sattler, R. De Jong, B. Druker, N. Heisterkamp, Bo Chen Lan Bo Chen, J. Groffen, J. D. Griffin

Research output: Contribution to journalArticle

121 Scopus citations

Abstract

The Philadelphia chromosome translocation generates a chimeric oncogene, BCR/ABL, which causes chronic myelogenous leukemia (CML). In primary neutrophils from patients with CML, the major novel tyrosine-phosphorylated protein is CRKL, an SH2-SH3-SH3 linker protein which has an overall homology of 60% to CRK, the human homologue of the v-crk oncogene product. Anti-CRKL immunoprecipitates from CML cells, but not normal cells, were found to contain p210(BCR/ABL) and c-ABL. Several other phosphoproteins were also detected in anti-CRKL immunoprecipitates, one of which has been identified as paxillin, a 68-kDa focal adhesion protein which we have previously shown to be phosphorylated by p210(BCR/ABL). Using GST-CRKL fusion proteins, the SH3 domains of CRKL were found to bind c-ABL and p210(BCR/ABL), while the SH2 domain of CRKL bound to paxillin, suggesting that CRKL could physically link p210(BCR/ABL) to paxillin. Paxillin contains three tyrosines in Tyr-X-X-Pro (Y-X-X-P) motifs consistent with amino acid sequences predicted to be optimal for binding to the CRKL-SH2 domain (at positions Tyr-31, Tyr-118, and Tyr- 181). Each of these tyrosine residues was mutated to a phenylalanine residue, and in vitro binding assays indicated that paxillin tyrosines at positions 31 and 118, but not 181, are likely to be involved in CRKL-SH2 binding. These results suggest that the p210(BCR/ABL) oncogene may be physically linked to the focal adhesion-associated protein paxillin in hematopoietic cells by CRKL. This interaction could contribute to the known adhesive defects of CML cells.

Original languageEnglish (US)
Pages (from-to)29145-29150
Number of pages6
JournalJournal of Biological Chemistry
Volume270
Issue number49
DOIs
StatePublished - Jan 1 1995

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Salgia, R., Uemura, N., Okuda, K., Li, J. L., Pisick, E., Sattler, M., De Jong, R., Druker, B., Heisterkamp, N., Lan Bo Chen, B. C., Groffen, J., & Griffin, J. D. (1995). CRKL links p210(BCR/ABL) with paxillin in chronic myelogenous leukemia cells. Journal of Biological Chemistry, 270(49), 29145-29150. https://doi.org/10.1074/jbc.270.49.29145