v-Abl signaling disrupts SOCS-1 function in transformed pre-B cells

André Limnander, Nika N. Danial, Paul B. Rothman

Research output: Contribution to journalArticlepeer-review

Abstract

The v-Abl oncogene activates Jak-Stat signaling during transformation of pre-B cells in mice. Disrupting Jak activation by deleting the Jak binding domain of v-Abl or by expressing a dominant-negative Jak1 decreases v-Abl transformation efficiency. As SOCS-1 is a known potent inhibitor of Jak kinases, the mechanism by which v-Abl bypasses SOCS-1 regulation to constitutively activate Jak kinases was investigated. SOCS-1 is expressed in v-Abl-transformed cells but is unable to inhibit v-Abl-mediated Jak-Stat signaling. In v-Abl transformants, SOCS-1 can inhibit cytokine signals, but it is more efficient at doing so when the cells are treated with STI571, an Abl kinase inhibitor. Downstream effects of v-Abl signaling include phosphorylation of SOCS-1 on nontyrosine residues, disruption of the interaction between SOCS-1 and the Elongin BC complex, and inhibition of SOCS-1-mediated proteasomal targeting of activated Jaks. These findings reveal a mechanism by which Jak-dependent oncogenes may bypass SOCS-1 inhibition.

Original languageEnglish (US)
Pages (from-to)329-341
Number of pages13
JournalMolecular cell
Volume15
Issue number3
DOIs
StatePublished - Aug 13 2004

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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