PMID- 22442148
OWN - NLM
STAT- MEDLINE
DCOM- 20120713
LR  - 20211021
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 287
IP  - 20
DP  - 2012 May 11
TI  - Signal transducer and activator of transcription 5b (Stat5b) serine 193 is a 
      novel cytokine-induced phospho-regulatory site that is constitutively activated 
      in primary hematopoietic malignancies.
PG  - 16596-608
LID - 10.1074/jbc.M111.319756 [doi]
AB  - Signal transducer and activator of transcription 5b (Stat5b) is a critical node 
      in the signaling network downstream of external (cytokines or growth factors) or 
      internal (oncogenic tyrosine kinases) stimuli. Maximum transcriptional activation 
      of Stat5b requires both tyrosine and serine phosphorylation. Although the 
      mechanisms governing tyrosine phosphorylation and activation of Stat5b have been 
      extensively studied, the role of serine phosphorylation remains to be fully 
      elucidated. Using mass spectrometry and phospho-specific antibodies, we 
      identified Ser-193 as a novel site of cytokine-induced phosphorylation within 
      human Stat5b. Stat5b Ser(P)-193 was detected in activated primary human 
      peripheral blood mononuclear cells or lymphoid cell lines in response to several 
      gamma common (gammac) cytokines, including interleukin (IL)-2, IL-7, IL-9, and IL-15. 
      Kinetic and spatial analysis indicated that Stat5b Ser-193 phosphorylation was 
      rapid and transient and occurred in the cytoplasmic compartment of the cell prior 
      to Stat5b translocation to the nucleus. Moreover, inducible Stat5b Ser-193 
      phosphorylation was sensitive to inhibitors of mammalian target of rapamycin 
      (mTOR), whereas inhibition of protein phosphatase 2A (PP2A) induced 
      phosphorylation of Ser-193. Reconstitution assays in HEK293 cells in conjunction 
      with site-directed mutagenesis, EMSA, and reporter assays indicated that 
      Ser(P)-193 is required for maximal Stat5b transcriptional activity. Indeed, 
      Stat5b Ser-193 was found constitutively phosphorylated in several lymphoid tumor 
      cell lines as well as primary leukemia and lymphoma patient tumor cells. Taken 
      together, IL-2 family cytokines tightly control Stat5b Ser-193 phosphorylation 
      through a rapamycin-sensitive mechanism. Furthermore, constitutive Ser-193 
      phosphorylation is associated with Stat5b proto-oncogenic activity and therefore 
      may serve as a novel therapeutic target for treating hematopoietic malignancies.
FAU - Mitra, Abhisek
AU  - Mitra A
AD  - Department of Biological Sciences and Border Biomedical Research Center, The 
      University of Texas, El Paso, Texas 79968, USA.
FAU - Ross, Jeremy A
AU  - Ross JA
FAU - Rodriguez, Georgialina
AU  - Rodriguez G
FAU - Nagy, Zsuzsanna S
AU  - Nagy ZS
FAU - Wilson, Harry L
AU  - Wilson HL
FAU - Kirken, Robert A
AU  - Kirken RA
LA  - eng
GR  - G12 MD007592/MD/NIMHD NIH HHS/United States
GR  - G12MD007592/MD/NIMHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120322
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Cytokines)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (STAT5 Transcription Factor)
RN  - 0 (STAT5B protein, human)
RN  - 452VLY9402 (Serine)
SB  - IM
MH  - Active Transport, Cell Nucleus/genetics
MH  - Cell Nucleus/genetics/*metabolism/pathology
MH  - Cytokines/genetics/*metabolism
MH  - HEK293 Cells
MH  - Hematologic Neoplasms/genetics/*metabolism/pathology
MH  - Humans
MH  - Leukocytes, Mononuclear/metabolism/pathology
MH  - Phosphorylation/genetics
MH  - Proto-Oncogene Proteins/genetics/*metabolism
MH  - STAT5 Transcription Factor/genetics/*metabolism
MH  - Serine/genetics/metabolism
PMC - PMC3351328
EDAT- 2012/03/24 06:00
MHDA- 2012/07/14 06:00
PMCR- 2013/05/11
CRDT- 2012/03/24 06:00
PHST- 2012/03/24 06:00 [entrez]
PHST- 2012/03/24 06:00 [pubmed]
PHST- 2012/07/14 06:00 [medline]
PHST- 2013/05/11 00:00 [pmc-release]
AID - S0021-9258(20)60795-5 [pii]
AID - M111.319756 [pii]
AID - 10.1074/jbc.M111.319756 [doi]
PST - ppublish
SO  - J Biol Chem. 2012 May 11;287(20):16596-608. doi: 10.1074/jbc.M111.319756. Epub 
      2012 Mar 22.