A mutant signal transducer and activator of transcription 5b, associated with growth hormone insensitivity and insulin-like growth factor-I deficiency, cannot function as a signal transducer or transcription factor.

Abstract

CONTEXT:

A natural missense mutation in the signal transducer and activator of transcription (STAT) 5b gene was recently identified in association with a female patient presenting with severe growth failure and immune dysfunction. The mutation results in an alanine to proline substitution at residue 630 (A630P) in the src-homology-2 domain, a region essential for docking of STATs to phospho-tyrosines on activated receptors, STAT dimerization, and stabilization of phospho-STAT-DNA interactions.

OBJECTIVE:

The purpose of this study was to explore the molecular mechanisms underlying the GH insensitivity and IGF-I deficiency caused by the A630P-mutated STAT5b.

RESULTS:

In reconstitution experiments using HEK293 cells, both GH and interferon-gamma were unable to activate mutant STAT5b (A630P), as demonstrated by lack of immunodetectable phospho-tyrosyl-STAT5b (A630P) and inability to drive luciferase reporter activity. However, the Src family of nonreceptor kinases [constitutively active v-src and epithelial growth factor-induced c-src] tyrosine-phosphorylated STAT5b(A630P). The v-src-induced phospho-STAT5b(A630P) translocated to the nucleus but, unlike wild-type Stat5b, was unable to bind DNA.

CONCLUSIONS:

The A630P mutation disrupts the src-homology-2 architecture such that: 1) mutant STAT5b most likely cannot dock to phospho-tyrosines on ligand-activated receptors; and 2) stable interactions with DNA are prevented. Because STAT5b (A630P) is an inefficient signal transducer and transcription factor, the detrimental impact on signaling pathways important for normal growth and immunity explains, in part, the complex clinical phenotype of GH insensitivity and immune dysfunction.

• Authors: Peng Fang, Eric M Kofoed, Brian M Little, Xiangdong Wang, Richard J M Ross, Stuart J Frank, Vivian Hwa, Ron G Rosenfeld
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 91 Issue 4 Pg. 1526-34 (Apr 2006) ISSN: 0021-972X [Print] United States
• PMID: 16464942 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Cytokines
• STAT5 Transcription Factor
• Transcription Factors
• Human Growth Hormone
• Insulin-Like Growth Factor I
• Interferon-gamma
• DNA
• Protein Tyrosine Phosphatases

Topics

• Adenoviridae (genetics)
• Blotting, Western
• Cell Line
• Cytokines (biosynthesis, genetics)
• DNA (biosynthesis, genetics)
• Electrophoretic Mobility Shift Assay
• Fibroblasts (metabolism)
• Genes, src (genetics, physiology)
• Genetic Vectors
• Human Growth Hormone (physiology)
• Humans
• Immunohistochemistry
• Insulin-Like Growth Factor I (deficiency)
• Interferon-gamma (metabolism)
• Mutation (physiology)
• Mutation, Missense (genetics)
• Phosphorylation
• Plasmids (genetics)
• Protein Tyrosine Phosphatases (metabolism)
• STAT5 Transcription Factor (genetics, physiology)
• Signal Transduction (genetics, physiology)
• Transcription Factors (genetics, physiology)
• Transfection