Semaphorin receptors meet receptor tyrosine kinases on the way of tumor progression

Semaphorins are extracellular signals known to guide migrating cells during developmental morphogenesis and in adult tissues. Semaphorin receptors, that is plexins and neuropilins, have been found in association with diverse receptor tyrosine kinases (RTKs), such as Met, ErbB2 and VEGFR2. These receptor complexes are formed in a cell-specific manner and can mediate distinctive signalling cascades, sometimes leading to divergent functional outcomes. This is particularly intriguing in cancer, since the same semaphorin has been found to mediate either tumor-promoting or tumor-suppressing functions, depending on the cancer type and cellular context. We will therefore review the current understanding about the role of RTKs in neuropilin and plexin signalling, putatively accounting for the multifaceted role of semaphorins in cancer.