Epithelial Src homology region 2 domain–containing phosphatase‐1 restrains intestinal growth, secretory cell differentiation, and tumorigenesis

A conserved noncatalytic domain SH2 (for src homology region 2) is located immediately N terminal to the kinase domains of all cytoplasmic protein-tyrosine kinases. We found that the wild-type v-fps SH2 domain stimulated the enzymatic activity of the adjacent kinase domain 10-fold and functioned as a powerful positive effector of catalytic and transforming activities within the v-fps oncoprotein (P130gag-fps). Partial proteolysis of P130gag-fps and supporting genetic data indicated that the v-fps SH2 domain exerts its effect on catalytic activity through an intramolecular interaction with the kinase domain. Amino acid alterations in the SH2 domain that impaired kinase function interfered with association of the SH2 domain with the kinase domain. Deletion of a conserved octapeptide motif converted the v-fps SH2 domain from an activator to an inhibitor of tyrosine kinase activity. This latent inhibitory activity of v-fps SH2 has functional implications for phospholipase C-gamma and p21ras GTPase-activating protein, both of which have two distinct SH2 domains suggestive of complex regulation. In addition to regulating the specific activity of the kinase domain, the SH2 domain of P130gag-fps was also found to be required for the tyrosine phosphorylation of specific cellular proteins, notably polypeptides of 124 and 62 kilodaltons. The SH2 domain therefore appears to play a dual role in regulation of kinase activity and recognition of cellular substrates.

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Src homology region 2 domains direct protein-protein interactions in signal transduction.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.87.21.8622 ◽

1990 ◽

Vol 87 (21) ◽

pp. 8622-8626 ◽

Cited By ~ 243

Author(s):

M. F. Moran ◽

C. A. Koch ◽

D. Anderson ◽

C. Ellis ◽

L. England ◽

...

Keyword(s):

Signal Transduction ◽

Protein Interactions ◽

Protein Protein Interactions ◽

Homology Region ◽

Src Homology

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BCR first exon sequences specifically activate the BCR/ABL tyrosine kinase oncogene of Philadelphia chromosome-positive human leukemias.

Molecular and Cellular Biology ◽

10.1128/mcb.11.4.1785 ◽

1991 ◽

Vol 11 (4) ◽

pp. 1785-1792 ◽

Cited By ~ 250

Author(s):

A J Muller ◽

J C Young ◽

A M Pendergast ◽

M Pondel ◽

N R Landau ◽

...

Keyword(s):

Tyrosine Kinase ◽

Cell Transformation ◽

Philadelphia Chromosome ◽

Sh3 Domain ◽

Kinase Domain ◽

Chromosome Translocation ◽

Regulatory Domains ◽

Homology Region ◽

Abl Tyrosine Kinase ◽

Src Homology

The c-abl proto-oncogene encodes a cytoplasmic tyrosine kinase which is homologous to the src gene product in its kinase domain and in the upstream kinase regulatory domains SH2 (src homology region 2) and SH3 (src homology region 3). The murine v-abl oncogene product has lost the SH3 domain as a consequence of N-terminal fusion of gag sequences. Deletion of the SH3 domain is sufficient to render the murine c-abl proto-oncogene product transforming when myristylated N-terminal membrane localization sequences are also present. In contrast, the human BCR/ABL oncogene of the Philadelphia chromosome translocation has an intact SH3 domain and its product is not myristylated at the N terminus. To analyze the contribution of BCR-encoded sequences to BCR/ABL-mediated transformation, the effects of a series of deletions and substitutions were assessed in fibroblast and hematopoietic-cell transformation assays. BCR first-exon sequences specifically potentiate transformation and tyrosine kinase activation when they are fused to the second exon of otherwise intact c-ABL. This suggests that BCR-encoded sequences specifically interfere with negative regulation of the ABL-encoded tyrosine kinase, which would represent a novel mechanism for the activation of nonreceptor tyrosine kinase-encoding proto-oncogenes.

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