Kinase-dependent and -independent roles of EphA2 in the regulation of prostate cancer invasion and metastasis.
Ligand-activated Eph tyrosine kinases regulate cellular repulsion, morphology, adhesion, and motility. EphA2 kinase is frequently up-regulated in several different types of cancers, including prostate, breast, colon, and lung carcinomas, as well as in melanoma. The existing data do not clarify whether EphA2 receptor phosphorylation or its simple overexpression, which likely leads to Eph kinase-independent responses, plays a role in the progression of malignant prostate cancer. In this study, we address the role of EphA2 tyrosine phosphorylation in prostate carcinoma cell adhesion, motility, invasion, and formation of metastases. Tumor cells expressing kinase-deficient EphA2 mutants, as well as an EphA2 variant lacking the cytoplasmic domain, are defective in ephrinA1-mediated cell rounding, retraction fiber formation, de-adhesion from the extracellular matrix, RhoA and Rac1 GTPase regulation, three-dimensional matrix invasion, and in vivo metastasis, suggesting a key role for EphA2 kinase activity. Nevertheless, EphA2 regulation of cell motility and invasion, as well as the formation of bone and visceral tumor colonies, reveals a component of both EphA2 kinase-dependent and -independent features. These results uncover a differential requirement for EphA2 kinase activity in the regulation of prostate carcinoma metastasis outcome, suggesting that although the kinase activity of EphA2 is required for the regulation of cell adhesion and cytoskeletal rearrangement, some distinct kinase-dependent and -independent pathways likely cooperate to drive cancer cell migration, invasion, and metastasis outcome.
Taddei
Maria Letizia
ML
Department of Biochemical Sciences, University of Florence, viale Morgagni 50, 50134 Florence, Italy.
Parri
Matteo
M
Angelucci
Adriano
A
Onnis
Barbara
B
Bianchini
Francesca
F
Giannoni
Elisa
E
Raugei
Giovanni
G
Calorini
Lido
L
Rucci
Nadia
N
Teti
Anna
A
Bologna
Mauro
M
Chiarugi
Paola
P
D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D036382:Ephrin-A1 / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000503:physiopathology*; D009362:Neoplasm Metastasis / Q000473:pathology / Q000503:physiopathology*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D036104:Receptor, EphA2 / Q000378:metabolism*
D036382:Ephrin-A1; D036104:Receptor, EphA2