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Kos1, a nonreceptor tyrosine kinase that suppresses Ras signaling
Kishalay Hoare1, Sarasija Hoare, Orla M Smith
1University of Florida Shands Cancer Center, 1600 SW Archer Road, Gainesville, FL 32610-0232, USA.
Abstract:
Kinase of embryonic stem cells (Kos1), a nonreceptor protein tyrosine kinase (NRPTK), was identified and cloned from differentiating murine embryonic stem cells. Kos1 is localized on mouse chromosome 11 that corresponds to human chromosome 17p13.1 and is homologous to Tnk1, Ack1 and Ack2, making it a new member of the Ack family of NRPTKs. Kos1 is a ubiquitously expressed 47-kDa protein with autotyrosine kinase activity that is developmentally regulated during embryogenesis. Kos1 is also upregulated following IL3 withdrawal from factor-dependent murine NSF/N1.H7 cells that undergo apoptosis, suggesting a role in growth inhibition. Stable overexpression of Kos1 inhibits growth of NIH 3T3 cells, while the kinase-dead Kos1(CN) promotes cell growth in both liquid culture and soft agar. In addition, forced expression of Kos1 inhibits Ras activity in an indirect mechanism that results in the downregulation of the Ras-Raf1-MAPK growth pathway. Furthermore, overexpression of Kos1 in NCI-H82 lung cancer cells that express oncogenic Ha-Ras(G12V) inhibits cell growth under reduced serum (0.5%) conditions in close association with the upregulation of the Ras inhibitor, Rap1A. Collectively, these data support a negative regulatory role for Kos1 in regulating the Ras-Raf1-MAPK growth pathway by a mechanism that requires its autotyrosine kinase activity.
Insights
Kinase of embryonic stem cells (Kos1), a novel protein tyrosine kinase, negatively regulates cell growth by inhibiting the Ras-Raf1-MAPK pathway. Its kinase activity is crucial for this tumor-suppressive function.
Area of Science:
- Molecular Biology
- Cell Signaling
- Cancer Research
Background:
- Kinase of embryonic stem cells (Kos1) is a newly identified nonreceptor protein tyrosine kinase (NRPTK).
- Kos1 belongs to the Ack family of NRPTKs and is developmentally regulated during embryogenesis.
Purpose of the Study:
- To investigate the role of Kos1 in cell growth regulation.
- To elucidate the mechanism by which Kos1 affects the Ras-Raf1-MAPK pathway.
Main Methods:
- Cloning and characterization of Kos1 from murine embryonic stem cells.
- Overexpression studies in NIH 3T3 and NCI-H82 lung cancer cells.
- Analysis of Ras activity and downstream signaling components.
Main Results:
- Overexpression of wild-type Kos1 inhibited cell growth, while kinase-dead Kos1 promoted it.
- Kos1 negatively regulated Ras activity and downregulated the Ras-Raf1-MAPK pathway.
- Kos1 overexpression in lung cancer cells reduced growth under low serum conditions, associated with Rap1A upregulation.
Conclusions:
- Kos1 acts as a negative regulator of cell growth.
- Kos1's tumor-suppressive function is mediated by its autotyrosine kinase activity.
- Kos1 inhibits the Ras-Raf1-MAPK pathway, suggesting its potential as a therapeutic target in cancers driven by this pathway.