title: Phosphoproteomic screen identifies potential therapeutic targets in melanoma.
abstract: Therapies directed against receptor tyrosine kinases are effective in many cancer subtypes, including lung and breast cancer. We used a phosphoproteomic platform to identify active receptor tyrosine kinases that might represent therapeutic targets in a panel of 25 melanoma cell strains. We detected activated receptors including TYRO3, AXL, MERTK, EPHB2, MET, IGF1R, EGFR, KIT, HER3, and HER4. Statistical analysis of receptor tyrosine kinase activation as well as ligand and receptor expression indicates that some receptors, such as FGFR3, may be activated via autocrine circuits. Short hairpin RNA knockdown targeting three of the active kinases identified in the screen, AXL, HER3, and IGF1R, inhibited the proliferation of melanoma cells and knockdown of active AXL also reduced melanoma cell migration. The changes in cellular phenotype observed on AXL knockdown seem to be modulated via the STAT3 signaling pathway, whereas the IGF1R-dependent alterations seem to be regulated by the AKT signaling pathway. Ultimately, this study identifies several novel targets for therapeutic intervention in melanoma.
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Tworkoski
authors.forename: Garima
authors.initials: G
authors.lastname: Singhal
authors.forename: Sebastian
authors.initials: S
authors.lastname: Szpakowski
authors.forename: Christina Ivins
authors.initials: CI
authors.lastname: Zito
authors.forename: Antonella
authors.initials: A
authors.lastname: Bacchiocchi
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Muthusamy
authors.forename: Marcus
authors.initials: M
authors.lastname: Bosenberg
authors.forename: Michael
authors.initials: M
authors.lastname: Krauthammer
authors.forename: Ruth
authors.initials: R
authors.lastname: Halaban
authors.forename: David F
authors.initials: DF
authors.lastname: Stern
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D007231:Infant, Newborn; D008544:Melanocytes / Q000201:enzymology; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D040901:Proteomics; D034741:RNA, Small Interfering / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017527:Receptor, IGF Type 2 / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology*
chemical_list: D010750:Phosphoproteins; D034741:RNA, Small Interfering; D017527:Receptor, IGF Type 2; D050796:STAT3 Transcription Factor; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases