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Disease specificity of kinase domains: the src-encoded catalytic domain converts erbB into a sarcoma oncogene
1Department of Molecular Biology and Microbiology, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA.
Abstract:
src and erbB are two tyrosine kinase-encoding oncogenes carried by retroviruses, which have distinct disease specificities. The former induces predominantly sarcomas, and the latter, leukemias. Src and ErbB have similar catalytic domains but have very different regulatory domains. A wealth of information exists concerning how different regulatory domains [Src homology 2 (SH2) and SH3 domains and autophosphorylation sites] control substrate and disease specificities. Whether the catalytic domain helps determine these specificities remains to be explored. Here we show that the Src catalytic domain is enzymatically active when substituted into the ErbB backbone and interacts with the ErbB regulatory domain. This ErbB/Src chimera displays autophosphorylation and substrate phosphorylation patterns different from those of both Src and ErbB. Neither SH2 and SH3 nor autophosphorylation sites are required for the Src catalytic domain to exert its fibroblast transforming ability. Most significantly, the catalytic domain can convert erbB from a leukemogenic oncogene into a sarcomagenic oncogene, suggesting that the leukemogenic determinants in part reside within the ErbB catalytic domain.
Insights
The Src catalytic domain, when placed in ErbB, alters oncogene specificity. This suggests that the catalytic domain, not just regulatory parts, influences cancer-causing abilities of oncogenes like Src and ErbB.
Area of Science:
- Oncogene research
- Molecular biology
- Cancer genetics
Background:
- Src and ErbB are tyrosine kinase oncogenes with distinct disease specificities: sarcomas and leukemias, respectively.
- While regulatory domains of Src and ErbB are well-studied, the role of their catalytic domains in determining specificity is less understood.
Purpose of the Study:
- To investigate whether the catalytic domain of Src influences oncogene specificity when incorporated into the ErbB backbone.
- To determine if the Src catalytic domain can alter the disease specificity of the ErbB oncogene.
Main Methods:
- Construction of an ErbB/Src chimera by substituting the Src catalytic domain into the ErbB protein.
- Analysis of the chimera's enzymatic activity, autophosphorylation, and substrate phosphorylation patterns.
- Assessment of the requirement for Src's regulatory domains (SH2, SH3, autophosphorylation sites) for fibroblast transformation.
Main Results:
- The Src catalytic domain remained enzymatically active within the ErbB backbone and interacted with ErbB's regulatory domain.
- The ErbB/Src chimera exhibited distinct autophosphorylation and substrate phosphorylation profiles compared to both native Src and ErbB.
- The fibroblast-transforming ability of the Src catalytic domain did not require its SH2, SH3, or autophosphorylation sites.
- The Src catalytic domain converted the leukemogenic ErbB oncogene into a sarcomagenic one.
Conclusions:
- The catalytic domain of Src plays a significant role in determining oncogene specificity.
- Leukemogenic determinants can reside within the catalytic domain of the ErbB oncogene.
- Oncogene specificity is influenced by both catalytic and regulatory domains, challenging previous assumptions.