The therapeutic potential of neurofibromin signaling pathways and binding partners

Abstract

Neurofibromin controls many cell processes, such as growth, learning, and memory. If neurofibromin is not working properly, it can lead to health problems, including issues with the nervous, skeletal, and cardiovascular systems and cancer. This review examines neurofibromin's binding partners, signaling pathways and potential therapeutic targets. In addition, it summarizes the different post-translational modifications that can affect neurofibromin's interactions with other molecules. It is essential to investigate the molecular mechanisms that underlie neurofibromin variants in order to provide with functional connections between neurofibromin and its associated proteins for possible therapeutic targets based on its biological function.

Fig. 1. Neurofibromin domains and interacting partners.

CSRD (cysteine-serine rich domain, residues 543–909), TBD (tubulin-binding domain, residues 1095–1197), GRD (GAP-related domain, residues 1198–1530), Sec14-PH (residues 1560–1816), LRD (leucine-rich domain, residues 1579–1971), the CTD (C-terminal domain, residues 2260–2818) including the NLS (bipartite nuclear localization signal domain, residues 2534–2550) and SBR (syndecan-binding region, residues 1357–1473 and 2619–2719). Domains are in bold whereas interacting partners are shown in colored boxes according to their cognate domains.

Fig. 2. Signaling proteins upstream of neurofibromin.

The APP and GM-CSFR, several RTKs and several GPCRs have been involved in neurofibromin signaling and with different biological consequences. Main cytosolic upstream regulators of neurofibromin include 14-3-3, FAK, PKC, PKA, DDAH1 and Spred1. Neurofibromin posttranslational modifications include phosphorylation and ubiquitination.

Fig. 3. Signaling pathways downstream of neurofibromin.

Neurofibromin is involved in several cell signaling pathways, including the Ras/MAPK, Akt/mTOR, Ral, ROCK/LIMK/cofilin, and cAMP/PKA pathways. From the cytosol to the nucleus neurofibromin regulates many fundamental cellular processes, such as expression of estrogen response genes, proliferation, migration, cortex development, learning and memory (L/M).

Fig. 4. Hippo, JAK/STAT and dopamine signaling pathways are regulated by neurofibromin.

a The Hippo pathway is a master regulator of tissue homeostasis and organ size in which MST1/2, LATS1/2 and YAP/TAZ are major players. The JAK/STAT pathway regulates embryonic development and is involved in processes such as stem cell maintenance, hematopoietic and inflammatory response. These pathways also regulate gene expression implicated in tumorigenesis and cancer progression. b This pathway involves neurofibromin in regulating cAMP levels, important in neuronal connections in which dopamine travels to areas of the brain and body to convey important information such as executive thinking, cognition, feelings of reward and pleasure and voluntary motor movements. Dopamine is thought to guide learning via dynamic and differential modulation of PKA.

Fig. 5. Neurofibromin therapeutic inhibitors and potential targets.

The identification of key regulatory neurofibromin partners may have important clinical implications, in a strategy aimed at blocking its inactivation and/or upregulating the protein. These benefits may extend beyond therapies relevant to neurofibromin to serve as a potential clinical strategy to attenuate the Ras pathway in tumors harboring variants in genes that function upstream of Ras. Inhibitors and potential targets are shown in red.