SHP-1 suppresses cancer cell growth by promoting degradation of JAK kinases.
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.
Wu
Chengyu
C
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Guan
Qin
Q
Wang
Yingjian
Y
Zhao
Z Joe
ZJ
Zhou
G Wayne
GW
D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D002455:Cell Division; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D015536:Down-Regulation; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D053613:Janus Kinase 1; D007938:Leukemia / Q000201:enzymology / Q000473:pathology*; D007976:Leupeptins / Q000494:pharmacology; D008223:Lymphoma / Q000201:enzymology / Q000473:pathology*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D053634:TYK2 Kinase; D014162:Transfection; D014407:Tumor Cells, Cultured; D018909:src Homology Domains
D015853:Cysteine Proteinase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D007976:Leupeptins; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D053634:TYK2 Kinase; C070139:TYK2 protein, human; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde