The SH2 domain-containing protein tyrosine phosphatase SHP-1 is induced by granulocyte colony-stimulating factor (G-CSF) and modulates signaling from the G-CSF receptor.
The SH2 domain-containing protein tyrosine phosphatase SHP-1 is expressed widely in the hematopoietic system. SHP-1 has been shown to negatively control signal transduction from many cytokine receptors by direct docking to either the receptor itself, or to members of the Jak family of tyrosine kinases which are themselves part of the receptor complex. Motheaten and viable motheaten mice, which are deficient in SHP-1, have increased myelopoiesis and show an accumulation of morphologically and phenotypically immature granulocytes, suggesting a role for SHP-1 in granulocytic differentiation. Here, we report that SHP-1 protein levels are up-regulated during the granulocyte colony-stimulating factor (G-CSF)-mediated granulocytic differentiation of myeloid 32D cells. Enforced expression of SHP-1 in these cells leads to decreased proliferation and enhanced differentiation, while introduction of a catalytically inactive mutant produces increased proliferation and results in a delay of differentiation. In vitro binding revealed that the SH2 domains of SHP-1 are unable to associate directly with tyrosine-phosphorylated G-CSF receptor (G-CSF-R). Furthermore, over-expression of SHP-1 in Ba/F3 cells expressing a G-CSF-R mutant lacking all cytoplasmic tyrosines also inhibited proliferation. Together, these data suggest that SHP-1 directly modulates G-CSF-mediated responses in hematopoietic cells via a mechanism that does not require docking to the activated G-CSF-R.
Institute of Hematology, Erasmus University Rotterdam, The Netherlands.
A C
AC
Ward
S P
SP
Oomen
L
L
Smith
J
J
Gits
D
D
van Leeuwen
A A
AA
Soede-Bobok
C A
CA
Erpelinck-Verschueren
T
T
Yi
I P
IP
Touw
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000187:drug effects / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects; D018909:src Homology Domains
D007377:Interleukin-3; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D011993:Recombinant Fusion Proteins; D016179:Granulocyte Colony-Stimulating Factor; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases