SHP-1 suppresses cancer cell growth by promoting degradation of JAK kinases

J Cell Biochem. 2003 Dec 1;90(5):1026-37. doi: 10.1002/jcb.10727.


SHP-1 has been proposed to be a tumor suppressor gene for several cancers. The expression of SHP-1 protein is diminished or abolished in most leukemia and lymphoma cell lines and tissues, and in some non-hematopoietic cancer cell lines, such as estrogen receptor (ER) negative breast cancer cell lines and some colorectal cancer cell lines. However, we do not know whether the reduced SHP-1 expression is the cause of cancer diseases or the secondary effect of cancer developments. Here, we first demonstrate that SHP-1 has general tumor suppressing function in SHP-1 transfected cell lines. Transfected SHP-1 inhibits the growth of three lymphoma/leukemia cell lines (Ramos, H9, Jurkat) and one breast cancer cell line (HTB26). We also demonstrate a possible molecular mechanism for the tumor suppressing function of SHP-1: SHP-1 inhibits cell growth partly by negative regulation of activated JAK kinase. In addition, we find, for the first time, that SHP-1 down-regulates the level of TYK2 kinase in H9 cells and of JAK1 kinase in HTB26 cells, by accelerating their degradation. The SHP-1 accelerated degradation of JAK1 kinase in HTB26 cells was blocked with the treatment of MG132, a specific inhibitor for proteasome-mediated proteolysis. Our data suggest a new function of SHP-1 in the regulation of proteasome-mediated degradation pathway.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Breast Neoplasms / enzymology
  • Breast Neoplasms / pathology*
  • Cell Division
  • Cysteine Proteinase Inhibitors / pharmacology
  • Down-Regulation
  • Female
  • Gene Expression Regulation, Enzymologic*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Janus Kinase 1
  • Leukemia / enzymology
  • Leukemia / pathology*
  • Leupeptins / pharmacology
  • Lymphoma / enzymology
  • Lymphoma / pathology*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases / pharmacology*
  • Protein-Tyrosine Kinases / metabolism*
  • TYK2 Kinase
  • Transfection
  • Tumor Cells, Cultured
  • src Homology Domains


  • Cysteine Proteinase Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Leupeptins
  • Protein-Tyrosine Kinases
  • JAK1 protein, human
  • Janus Kinase 1
  • TYK2 Kinase
  • TYK2 protein, human
  • PTPN6 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde