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Department of Physiology (L.S.S., J.A.V., A.S., J.S., C.C.-S.), University of Michigan Medical School, Ann Arbor, Michigan 49109-0622; Department of Neuroscience (Y.H.), The Cleveland Clinic Foundation, Cleveland, Ohio 44195; and Departments of Medicine and Microbiology and Immunology (G.L., L.-Y.Y.-L.), Baylor College of Medicine, Houston, Texas 77030
Address all correspondence and requests for reprints to: Christin Carter-Su, Department of Physiology, University of Michigan Medical School, Ann Arbor, Michigan 49109-0622.
GH is known to activate JAK2 tyrosine kinase and members of the Stat
family of transcription factors, including Stats 1, 3, and 5. The
recent observation that at least two Stat5 proteins (Stat5A and Stat5B)
exist in mouse and human, raises the question of whether GH activates
both Stat5A and Stat5B and, if so, whether the requirements for
activation are the same. An initial report investigating this issue
demonstrated GH-dependent activation of Stat5A but not Stat5B. In this
paper, we demonstrate (in COS cells expressing rat GH receptor (rGHR)
and either Stat5A or Stat5B, 3T3-F442A fibroblasts, and CHO cells
expressing rGHR) that GH induces tyrosyl phosphorylation of both Stat5A
and Stat5B. Similar time courses of phosphorylation were observed for
the two proteins. Interestingly, the pattern of observed bands differs
for the two forms of Stat5. Two closely migrating Stat5A bands can be
detected in cells treated with or without GH. Both of these bands
become tyrosyl phosphorylated in response to GH. Three species of
Stat5B are observed in untreated cells. An additional, more slowly
migrating Stat5B band, appears upon treatment with GH. The three more
slower migrating Stat5B bands observed in response to GH contain
phosphorylated tyrosyl residues. We further demonstrate that GH induces
binding of Stat5A and Stat5B, as well as Stat1, to the GAS-like element
in the ß-casein promoter. We and others have
demonstrated previously that specific regions of GHR are required for
GH-dependent activation of what is here identified as Stat5B. To gain
insight into the mechanism by which GH promotes tyrosyl phosphorylation
of Stat5A, GH-dependent tyrosyl phosphorylation of Stat5A was examined
in CHO cells expressing truncated and mutated rGHR. The results
indicate that Stat5A and Stat5B require the same regions of rGHR for
maximal activation by GH: the C-terminal half of the cytoplasmic
domain; tyrosines 333 and/or 338 in the N-terminal half of the
cytoplasmic domain; and the regions required for JAK2 activation. To
dissect further the mechanism by which GH activates Stat5A and B, the
requirement for JAK2 in GH-dependent Stat5 tyrosyl phosphorylation was
assessed using JAK2-deficient cells expressing GHR (
2A-GHR) and the
wild-type parental cell line expressing GHR (2C4-GHR). GH-induced
tyrosyl phosphorylation of Stat5B in 2C4-GHR cells but not in the JAK2
deficient, 2A-GHR cells, indicating that JAK2 is required for
GH-dependent tyrosyl phosphorylation of Stat5B. Western blotting
revealed that Stat5A is not expressed in this cell type. Taken
together, these findings suggest that: 1) GH activates both Stat5A and
Stat5B in several cell types; 2) the pattern of bands observed differs
for Stat5A and Stat5B; 3) GH-dependent tyrosyl phosphorylation of
Stat5A requires specific regions of GHR, and these requirements are the
same as for Stat5B; and 4) JAK2 kinase is required for GH-dependent
tyrosyl phosphorylation of Stat5B and, most likely, Stat5A.
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