Episodic Src activation in uveal melanoma revealed by kinase activity profiling.
BACKGROUND
The RAS/RAF/MEK/ERK pathway is involved in the balance between melanocyte proliferation and differentiation. The same pathway is constitutively activated in cutaneous and uveal melanoma (UM) and related to tumour growth and survival. Whereas mutant BRAF and NRAS are responsible for the activation of the RAS/RAF/MEK/ERK pathway in most cutaneous melanoma, mutations in these genes are usually absent in UM.


METHODS
We set out to explore the RAS/RAF/MEK/ERK pathway and used mitogen-activated protein kinase profiling and tyrosine kinase arrays.


RESULTS
We identified Src as a kinase that is associated with ERK1/2 activation in UM. However, low Src levels and reduced ERK1/2 activation in metastatic cell lines suggest that proliferation in metastases can become independent of Src and RAS/RAF/MEK/ERK signalling. Inhibition of Src led to the growth reduction of primary UM cultures and cell lines, whereas metastatic cell line growth was only slightly reduced.


CONCLUSIONS
We identified Src as an important kinase and a potential target for treatment in primary UM. Metastasis cell lines seemed largely resistant to Src inhibition and indicate that in metastases treatment, a different approach may be required.
Maat
W
W
Department of Ophthalmology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
el Filali
M
M
Dirks-Mulder
A
A
Luyten
G P M
GP
Gruis
N A
NA
Desjardins
L
L
Boender
P
P
Jager
M J
MJ
van der Velden
P A
PA
D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D006801:Humans; D008545:Melanoma / Q000201:enzymology* / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009362:Neoplasm Metastasis; D014604:Uveal Neoplasms / Q000201:enzymology* / Q000473:pathology; D019061:src-Family Kinases / Q000378:metabolism*
D019061:src-Family Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3