Rap1 activity is elevated in malignant astrocytomas independent of tuberous sclerosis complex-2 gene expression.

Increased small GTPase protein mitogenic signaling is common in tumors. We have previously demonstrated that sporadic astrocytomas exhibit high levels of activated Ras important for tumor growth. Individuals with tuberous sclerosis complex (TSC) develop astrocytoma-like tumors resulting from mutations in the TSC2 protein, tuberin, which is hypothesized to function as a Rap1 GTPase activating protein (GAP). Since we have previously reported that high-grade astrocytomas frequently exhibit loss of tuberin expression or increased Rap1 levels, we sought to determine whether there is a correlation between decreased tuberin Rap1-GAP function or Rap1 overexpression and tumor Rap1 activity. In this study, we compared levels of Rap1-GTP, Rap1 and tuberin levels in normal brain tissue and 24 grade II-IV astrocytoma specimens. Whereas Rap1 overexpression was observed in astrocytomas of all malignancy grades, tuberin loss was seen most frequently in the higher-grade astrocytomas. In the grade IV glioblastoma multiforme tumors, Rap1 activity was 2-3-fold higher than in lower grade or non-neoplastic brain. However, there was no correlation between tuberin expression or Rap1 overexpression and the levels of Rap1 activity in the tumors studied, suggesting that the increased Rap1 activation is not the direct result of reduced tuberin Rap1-GAP function or elevated Rap1 protein expression.