PMID- 10585430
OWN - NLM
STAT- MEDLINE
DCOM- 20000113
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 50
DP  - 1999 Dec 10
TI  - SOCS/CIS protein inhibition of growth hormone-stimulated STAT5 signaling by
      multiple mechanisms.
PG  - 35553-61
AB  - The inhibition of growth hormone (GH) signaling by five members of the
      GH-inducible suppressor of cytokine signaling (SOCS/CIS) family was investigated 
      in transfected COS cells. Complete inhibition of GH activation of the signal
      transducer STAT5b and STAT5b-dependent transcriptional activity was observed upon
      expression of SOCS-1 or SOCS-3, while partial inhibition (CIS, SOCS-2) or no
      inhibition (SOCS-6) was seen with other SOCS/CIS family members. SOCS-1, SOCS-2, 
      SOCS-3, and CIS each strongly inhibited the GH receptor (GHR)-dependent tyrosine 
      phosphorylation of JAK2 seen at low levels of transfected JAK2; however, only
      SOCS-1 strongly inhibited the GHR-independent tyrosine phosphorylation of JAK2
      seen at higher JAK2 levels. To probe for interactions with GHR, in vitro binding 
      assays were carried out using glutathione S-transferase-GHR fusion proteins
      containing variable lengths of GHR's COOH-terminal cytoplasmic domain. CIS and
      SOCS-2 bound to fusions containing as few as 80 COOH-terminal GHR residues,
      provided the fusion protein was tyrosine-phosphorylated. By contrast, SOCS-3
      binding required tyrosine-phosphorylated GHR membrane-proximal sequences, SOCS-1 
      binding was tyrosine phosphorylation-independent, and SOCS-6 did not bind the GHR
      fusion proteins at all. Mutation of GHR's membrane-proximal tyrosine residues 333
      and 338 to phenylalanine suppressed the inhibition by SOCS-3, but not by CIS, of 
      GH signaling to STAT5b. SOCS/CIS proteins can thus inhibit GH signaling to STAT5b
      by three distinct mechanisms, distinguished by their molecular targets within the
      GHR-JAK2 signaling complex, as exemplified by SOCS-1 (direct JAK2 kinase
      inhibition), SOCS-3 (inhibition of JAK2 signaling via membrane-proximal GHR
      tyrosines 333 and 338), and CIS and SOCS-2 (inhibition via membrane-distal
      tyrosine(s)).
FAU - Ram, P A
AU  - Ram PA
AD  - Department of Biology, Division of Cell Biology, Boston University, Boston,
      Massachusetts 02215, USA.
FAU - Waxman, D J
AU  - Waxman DJ
LA  - eng
GR  - R01 DK033765/DK/NIDDK NIH HHS/United States
GR  - DK33765/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Carrier Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Immediate-Early Proteins)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Milk Proteins)
RN  - 0 (Proteins)
RN  - 0 (Receptors, Somatotropin)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (Repressor Proteins)
RN  - 0 (SOCS1 protein, human)
RN  - 0 (SOCS2 protein, human)
RN  - 0 (SOCS3 protein, human)
RN  - 0 (STAT5 Transcription Factor)
RN  - 0 (STAT5B protein, human)
RN  - 0 (Socs1 protein, rat)
RN  - 0 (Socs2 protein, rat)
RN  - 0 (Socs3 protein, rat)
RN  - 0 (Stat5b protein, rat)
RN  - 0 (Suppressor of Cytokine Signaling 1 Protein)
RN  - 0 (Suppressor of Cytokine Signaling 3 Protein)
RN  - 0 (Suppressor of Cytokine Signaling Proteins)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcription Factors)
RN  - 0 (cytokine inducible SH2-containing protein)
RN  - 9002-72-6 (Growth Hormone)
SB  - IM
MH  - Animals
MH  - Carrier Proteins/*metabolism
MH  - Cell Line
MH  - Cloning, Molecular
MH  - DNA-Binding Proteins/genetics/*metabolism
MH  - Growth Hormone/*pharmacology
MH  - Humans
MH  - Hypophysectomy
MH  - Immediate-Early Proteins/*metabolism
MH  - *Intracellular Signaling Peptides and Proteins
MH  - Male
MH  - *Milk Proteins
MH  - Proteins/*metabolism
MH  - Rats
MH  - Rats, Inbred F344
MH  - Receptors, Somatotropin/drug effects/*physiology
MH  - Recombinant Fusion Proteins/drug effects/metabolism
MH  - *Repressor Proteins
MH  - STAT5 Transcription Factor
MH  - Signal Transduction/drug effects/*physiology
MH  - Suppressor of Cytokine Signaling 1 Protein
MH  - Suppressor of Cytokine Signaling 3 Protein
MH  - Suppressor of Cytokine Signaling Proteins
MH  - Trans-Activators/genetics/*metabolism
MH  - *Transcription Factors
MH  - Transfection
MH  - src Homology Domains
EDAT- 1999/12/10 00:00
MHDA- 1999/12/10 00:01
CRDT- 1999/12/10 00:00
PHST- 1999/12/10 00:00 [pubmed]
PHST- 1999/12/10 00:01 [medline]
PHST- 1999/12/10 00:00 [entrez]
AID - 10.1074/jbc.274.50.35553 [doi]
AID - S0021-9258(19)53281-1 [pii]
PST - ppublish
SO  - J Biol Chem. 1999 Dec 10;274(50):35553-61. doi: 10.1074/jbc.274.50.35553.