PMID- 10329850
OWN - NLM
STAT- MEDLINE
DCOM- 19990602
LR  - 20190723
IS  - 0091-6749 (Print)
IS  - 0091-6749 (Linking)
VI  - 103
IP  - 5 Pt 2
DP  - 1999 May
TI  - Differential influence of tyrosine residues of the common receptor beta subunit
      on multiple signals induced by human GM-CSF.
PG  - S462-70
AB  - BACKGROUND: GM-CSF induces the proliferation and differentiation of a broad range
      of hematopoietic cells. Stimulation with this cytokine results in the induction
      of rapid tyrosine phosphorylation of cellular proteins, including the common beta
      subunit of its receptor. However, the significance of beta subunit
      phosphorylation with regard to regulation of signaling molecules and the
      functions of GM-CSF is less well understood. OBJECTIVE: To investigate the role
      of cytoplasmic tyrosine residues, we performed mutational analyses of the beta
      subunit. METHODS: A series of beta subunit mutants with 1, some, or all of 8
      cytoplasmic tyrosines converted to phenylalanines were constructed. These beta
      subunit mutants were expressed in murine BA/F3 cells together with the wild-type 
      human alpha subunit, and their potentials to transmit signals were examined.
      RESULTS: A mutant beta subunit lacking all cytoplasmic tyrosines (Fall) activated
      JAK2, but not Shc, SHP-2, the Raf/ERK cascade, signal transducer and activator of
      transcription 5 (STAT5), or the c-fos promoter, nor did it effectively induce
      proliferation. Adding back each tyrosine to Fall revealed that (1) Tyr577 was
      necessary and sufficient for Shc phosphorylation; (2) Tyr577, Tyr612, and Tyr695 
      were involved in activation of SHP-2, the Raf/ERK cascade, and c-fos
      transcription; and (3) all tyrosines, but particularly Tyr612, Tyr695, Tyr750,
      and Tyr806, facilitated STAT5 activation. Impaired cell growth was also partly
      restored by any of the tyrosines. Interestingly, the Fall mutant was still
      capable of suppressing apoptosis and maintaining cell viability. CONCLUSION:
      These results provide evidence that beta subunit tyrosines possess distinct, yet 
      overlapping, roles in the activation of multiple signaling pathways induced by
      GM-CSF. In addition, GM-CSF may activate both beta subunit tyrosine-dependent and
      -independent pathways, with the latter being sufficient to transmit survival
      signals.
FAU - Itoh, T
AU  - Itoh T
AD  - Department of Molecular and Developmental Biology, The Institute of Medical
      Science, The University of Tokyo, Japan.
FAU - Liu, R
AU  - Liu R
FAU - Arai, K
AU  - Arai K
FAU - Watanabe, S
AU  - Watanabe S
LA  - eng
PT  - Journal Article
PL  - United States
TA  - J Allergy Clin Immunol
JT  - The Journal of allergy and clinical immunology
JID - 1275002
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Milk Proteins)
RN  - 0 (Receptors, Leukocyte-Adhesion)
RN  - 0 (STAT5 Transcription Factor)
RN  - 0 (Trans-Activators)
RN  - 42HK56048U (Tyrosine)
RN  - 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor)
SB  - AIM
SB  - IM
MH  - Animals
MH  - Cell Survival/drug effects
MH  - DNA-Binding Proteins/genetics
MH  - Gene Expression Regulation
MH  - Genes, fos/genetics
MH  - Granulocyte-Macrophage Colony-Stimulating Factor/*physiology
MH  - Humans
MH  - Mice
MH  - *Milk Proteins
MH  - Promoter Regions, Genetic/genetics
MH  - Receptors, Leukocyte-Adhesion/*drug effects
MH  - STAT5 Transcription Factor
MH  - Signal Transduction
MH  - Trans-Activators/genetics
MH  - Tyrosine/*physiology
EDAT- 1999/05/18 00:00
MHDA- 1999/05/18 00:01
CRDT- 1999/05/18 00:00
PHST- 1999/05/18 00:00 [pubmed]
PHST- 1999/05/18 00:01 [medline]
PHST- 1999/05/18 00:00 [entrez]
AID - S0091-6749(99)70163-6 [pii]
AID - 10.1016/s0091-6749(99)70163-6 [doi]
PST - ppublish
SO  - J Allergy Clin Immunol. 1999 May;103(5 Pt 2):S462-70. doi:
      10.1016/s0091-6749(99)70163-6.