Investigating the role of TAM family receptors in Merlin deficient tumours

Abstract

BACKGROUND

TAM (TYRO3, Axl and MER) family of receptor tyrosine kinase has been recognised to be upregulated in tumours of diverse origin. Moreover, they are shown to be under negative control of protein merlin, encoded by Neurofibromatosis type II (NF2) gene. Mutation of NF2 gene is responsible for the development of multiple nervous system tumours such as schwannomas, meningiomas and ependymomas. Conventional chemotherapy is ineffective for this group of tumours due to their benign nature, and surgery/radiosurgery carry significant risk due to the multiplicity and location of tumours, thus effective drug therapy is urgently needed.

METHODS

In this study, we are using schwannomas and meningiomas tumour lysates and primary cells to examine the functional and direct correlation of TAM family receptors using confocal microscopy, co-immunoprecipitation and lentivirus based knockdown experiments followed by western blot.

RESULTS AND CONCLUSIONS

Confocal microscopy revealed close association of all three receptors however, co-immunoprecipitation experiments showed direct interaction only between AXL and TYRO3 in schwannomas. Moreover, expression of AXL found to be dependent on TYRO3 and MER. Besides interaction with own members, TAM family receptors also interact with other receptor groups such as integrin β1. Moreover, meningiomas also showed overexpression of all three TAM members in grade-I tumours. Overexpression and activation of TYRO3, AXL and MER found in NF2-/- meningiomas primary cells and which could be reversed on Merlin reintroduction. Investigating the role of TAM family receptors in pathobiology of schwannoma and meningioma will help to determine the best molecule to target therapeutically for NF2 tumours.