Stimulation of the protein tyrosine kinase c-Yes but not c-Src by neurotrophins in human brain-metastatic melanoma cells

Dario Marchetti, Nila Parikh, Marius Sudol, Gary E. Gallick

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

The c-Yes proto-oncogene (pp62(c-Yes)) encodes a nonreceptor-type protein tyrosine kinase (NRPTK) of the Src family. c-Yes activities and protein levels are elevated in human melanoma and melanocyte cell lines. Because the neurotrophins (NT) are important in the progression of melanoma to the brain-metastatic phenotype, we determined, whether NT stimulate c-Yes activity in human MeWo melanoma cells and two variant sublines with opposite metastatic capabilities, 3 S 5 and 70W. The highly brain-metastatic 70W subline had an intrinsically higher c-Yes activity than parental MeWo or poorly metastatic 3S5 cells. c-Yes kinase was further induced by the prototypic human NT, nerve growth factor (NGF) in a dose and time-dependent manner. In contrast, c-Src activity (pp60(c-Src)) was similar in all these cells and unaffected by NGF exposure. Additionally, human NGF and neurotrophin-3 stimulated c-Yes in brain-metastatic 70W cells. The magnitude of cYes activation correlated with the degree of invasion of 70W cells following incubation of these neurotrophins. To further examine NT stimulation of c-Yes in melanoma cells, three additional cell lines were examined. Metastatic TXM-13 and TXM-18 increased c-Yes activity in response to NGF. In contrast, no increase was observed in low-metastatic TXM-40 cells. Together, these data suggest that altered c-Yes expression may play a role in the malignant progression of the human melanocyte towards the brain-metastatic phenotype and that NT enhance the activity of c-Yes in signaling penetration into the matrix of NT-rich stromal microenvironments such as the brain.

Original languageEnglish (US)
Pages (from-to)3253-3260
Number of pages8
JournalOncogene
Volume16
Issue number25
DOIs
StatePublished - Jun 25 1998

Keywords

  • Brain-metastatic melanoma
  • Nerve growth factor
  • Neurotrophin-3
  • Neurotrophins
  • c-Src
  • c-Yes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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