Abstract
Several proteins that contribute to epigenetic mechanisms of gene regulation contain a characteristic motif of unknown function called the SET (Suvar3-9, Enhancer-of-zeste, Trithorax) domain. We have demonstrated that SET domains mediate highly conserved interactions with a specific family of proteins that display similarity with dual-specificity phosphatases (dsPTPases). These include myotubularin, the gene of which is mutated in a subset of patients with X-linked myotubular myopathy, and Sbf1, a newly isolated homologue of myotubularin. In contrast with myotubularin, Sbf1 lacks a functional catalytic domain which dephosphorylates phospho-tyrosine and serine-containing peptides in vitro. Competitive interference of endogenous SET domain-dsPTPase interactions by forced expression of Sbf1 induced oncogenic transformation of NIH 3T3 fibroblasts and impaired the in vitro differentiation of C2 myoblast cells. We conclude that myotubularin-type phosphatases link SET-domain containing components of the epigenetic regulatory machinery with signalling pathways involved in growth and differentiation.
Publication types
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
3T3 Cells / cytology
-
3T3 Cells / metabolism
-
Amino Acid Sequence
-
Animals
-
Binding Sites
-
Carrier Proteins / genetics
-
Carrier Proteins / physiology*
-
Cell Differentiation / genetics
-
Cell Differentiation / physiology
-
Cell Division / physiology
-
Cell Transformation, Neoplastic / genetics
-
Chromosomal Proteins, Non-Histone
-
Conserved Sequence / genetics
-
Conserved Sequence / physiology
-
DNA-Binding Proteins
-
Histone Chaperones
-
Humans
-
Intracellular Signaling Peptides and Proteins*
-
Mice
-
Molecular Sequence Data
-
Myocardium / cytology
-
Myocardium / metabolism
-
Phosphoric Monoester Hydrolases / metabolism
-
Protein Binding
-
Protein Structure, Tertiary
-
Protein Tyrosine Phosphatases / genetics
-
Protein Tyrosine Phosphatases / physiology*
-
Protein Tyrosine Phosphatases, Non-Receptor
-
Proteins / chemistry
-
Proteins / isolation & purification
-
Proteins / metabolism*
-
Sequence Homology, Amino Acid
-
Transcription Factors
Substances
-
Carrier Proteins
-
Chromosomal Proteins, Non-Histone
-
DNA-Binding Proteins
-
Histone Chaperones
-
Intracellular Signaling Peptides and Proteins
-
Proteins
-
SBF1 protein, human
-
SET protein, human
-
Transcription Factors
-
Phosphoric Monoester Hydrolases
-
Protein Tyrosine Phosphatases
-
Protein Tyrosine Phosphatases, Non-Receptor
-
myotubularin