Merlin, a multi‐suppressor from cell membrane to the nucleus

Abstract

Edited by Wilhelm JustKeywords: NF2 Merlin DCAF1 Integrin RTK a b s t r a c t Recent evidence suggests that the neurofibromatosis type 2 (NF2) gene encoded protein merlin suppresses mitogenic signalling not only at the cell membrane but also in the nucleus. At the membrane, merlin inhibits signalling by integrins and tyrosine receptor kinases (RTKs) and the activation of downstream pathways, including the Ras/Raf/MEK/ERK, FAK/Src, PI3K/AKT, Rac/PAK/ JNK, mTORC1, and Wnt/b-catenin pathways. In the nucleus, merlin suppresses the E3 ubiquitin ligase CRL4 DCAF1 to inhibit proliferation. Gene expression analysis suggested that CRL4 DCAF1 could also regulate the expression of integrins and RTKs. In this review, we explore the links between merlin function at the membrane and in the nucleus, and discuss the potential of targeting the master regulator CRL4 DCAF1 to treat NF2 and other merlin-deficient tumours.

The Hippo Pathway Is Activated and Is a Causal Mechanism for Adipogenesis in Arrhythmogenic Cardiomyopathy

“…In conjunction with partial inactivation of pPKC-α, NF2 or Merlin, which is inactivated upon phosphorylation by pPKC-α, was activated in AC 2819 . Activation of NF2 was associated with cascade phosphorylation of the Hippo kinases, including MST1/2, LATS1/2, and YAP, the latter is the effector of the Hippo pathway, which is inactivated upon phosphorylation 20 . Consequently, gene expression through YAP-TEAD was suppressed.…”

“…The role of these changes in inactivation of the Hippo pathway was not characterized in the present study. Finally, the Hippo pathway molecules are typically tumor suppressor multi-functional proteins with diverse phenotypic effects 20 . Thus, it would not be surprising if alternative and complementary mechanisms activate the Hippo pathway in AC.…”

Neurofibromatosis-related tumors

“…The complex biology underlying Merlin’s functions, including tumor suppression and contact inhibition, remains incompletely understood and is beyond the scope of this article, but has been summarized in a number of excellent recent reviews [37] [38] [39]. …”

Polyneuropathies associated with neurofibromatosis

“…Neurofibromatosis 2 is caused by mutation of the NF2 gene on chromosome 22q12 that encodes for the tumor suppressor protein merlin (moesin-ezrin-radixin-like protein; synonym: schwannomin) [6]. Merlin regulates many cellular functions such as adhesion, cell motility, growth, proliferation, and survival by interacting with diverse pathways including receptor tyrosine kinases and integrins at the cell surface and ubiquitin E3 ligase activity in the nucleus [8].…”