Proteomic analysis of Src family kinase phosphorylation states in cancer cells suggests deregulation of the unique domain

Ana Ruiz-Saenz, Farima Zahedi, Elliott Peterson, Ashley Yoo, Courtney A. Dreyer, Danislav S. Spassov, Juan Oses-Prieto, Alma Burlingame, Mark M. Moasser*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)

Abstract

The Src family kinases (SFK) are homologs of retroviral oncogenes, earning them the label of proto-oncogenes. Their functions are influenced by positive and negative regulatory tyrosine phosphorylation events and inhibitory and activating intramolecular and extramolecular interactions. This regulation is disrupted in their viral oncogene counterparts. However, in contrast to most other proto-oncogenes, the genetic alteration of these genes does not seem to occur in human tumors and how and whether their functions are altered in human cancers remain to be determined. To look for proteomic-level alterations, we took a more granular look at the activation states of SFKs based on their two known regulatory tyrosine phosphorylations, but found no significant differences in their activity states when comparing immortalized epithelial cells with cancer cells. SFKs are known to have other less well-studied phosphorylations, particularly within their unstructured N-terminal unique domains (UD), although their role in cancers has not been explored. In comparing panels of epithelial cells with cancer cells, we found a decrease in S17 phosphorylation in the UD of Src in cancer cells. Dephosphorylated S17 favors the dimerization of Src that is mediated through the UD and suggests increased Src dimerization in cancers. These data highlight the important role of the UD of Src and suggest that a deeper understanding of proteomic-level alterations of the unstructured UD of SFKs may provide considerable insights into how SFKs are deregulated in cancers. Implications: This work highlights the role of the N-terminal UD of Src kinases in regulating their signaling functions and possibly in their deregulation in human cancers.

Original languageEnglish
Pages (from-to)957-967
Number of pages11
JournalMolecular Cancer Research
Volume19
Issue number6
DOIs
Publication statusPublished - Jun 2021

Bibliographical note

Funding Information:
We thank Nathaniel Gulizia, Courtney A. Dreyer, and Jennifer Merino for technical assistance. We acknowledge the use of the UCSF core facilities including the Cancer Center Laboratory for Cell Analysis core and the UCSF Biomedical Mass Spectrometry and Proteomics Resource Center. UCSF Mass Spectrometry Facility (A. Burlingame, director) was supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and NIH P41GM103481 and 1S10OD016229. A. Ruiz-Saenz was supported by a grant for postgraduate studies in Life and Matter Sciences of the Fundacion Ramon Areces. D.S. Spassov is currently receiving funding by the European Union?s Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie grant agreement no. 882247.

Funding Information:
A. Burlingame reports grants from Adelson Medical Research Foundation during the conduct of the study. No disclosures were reported by the other authors.

Funding Information:
We thank Nathaniel Gulizia, Courtney A. Dreyer, and Jennifer Merino for technical assistance. We acknowledge the use of the UCSF core facilities including the Cancer Center Laboratory for Cell Analysis core and the UCSF Biomedical Mass Spectrometry and Proteomics Resource Center. UCSF Mass Spectrometry Facility (A. Burlingame, director) was supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and NIH P41GM103481 and 1S10OD016229. A. Ruiz-Saenz was supported by a grant for postgraduate studies in Life and Matter Sciences of the Fundación Ramón Areces. D.S. Spassov is currently receiving funding by the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie grant agreement no. 882247.

Publisher Copyright:
2021 American Association for Cancer Research.

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