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The passive voice and the active voice: for example, is it a matter of “at” or “to?” The NF1 gene product, neurofibromin (Nfn), in its interaction with the oncoprotein, Ras, does something to the cell’s plasma membrane (PM); the reactions in question do not merely happen at the cell’s PM. Moreover, what the Nfn does to the PM in NF1 cells has been seriously underestimated because of yet another perspective issue. The vast majority of publications on the membrane-bound interaction of Nfn and Ras have been from the perspective that, first and foremost – if not exclusively – the NF1 gene is considered a “tumor suppressor gene.” This is rather narrow, respecting the ancient origin and very highly conserved nature of the NF1 alphabetical code, and the intuitive understanding that the vast majority of eukaryotic species are not at risk for tumors or cancer.
Open Journal PUBLISHERS Editorial Pathology Hiding in Plain Sight: The NF1 Plasma Membrane * Vincent M. Riccardi, MD, MBA* The Neurofibromatosis Institute, 5415 Briggs Avenue, La Crescenta, CA 91214, USA * *Corresponding author Vincent M. Riccardi, MD, MBA The Neurofibromatosis Institute, 5415 Briggs Avenue, La Crescenta, CA 91214, USA; E-mail: riccardi@medconsumer.com Article information th th th rd Received: February 19 , 2020; Revised: February 25 , 2020; Accepted: February 26 , 2020; Published: March 3 , 2020 Cite this article Riccardi VM. Pathology hiding in plain sight:The NF1 plasma membrane. Cancer Stud Mol Med Open J. 2020; 6(1): e1-e3. doi: 10.17140/CSMMOJ-6-e008 he passive voice and the active voice: for example, is it a mat- According to some authors, the only purpose of the ter of “at” or “to?” The NF1 gene product, neurofibromin Ras “oncoprotein” is to be a – if not the – critical determinant T (Nfn), in its interaction with the oncoprotein, Ras, does something of rapidly accelerated fibrosarcoma (Raf) activation and thereby to the cell’s plasma membrane (PM); the reactions in question do the key regulator of the MEK, mitogen-activated protein kinase not merely happen at the cell’s PM. Moreover, what the Nfn does (MAPK), extracellular signal-regulated kinase (ERK) cascade and 4-9 to the PM in NF1 cells has been seriously underestimated because their consequent regulatory networks.4-9 And almost all of the rel- of yet another perspective issue. The vast majority of publications evant literature regarding the physiological role and importance on the membrane-bound interaction of Nfn and Ras have been of Ras respects and amplifies this prejudice. Respecting that the from the perspective that, first and foremost – if not exclusively over-riding concern of some researchers is the development of – the NF1 gene is considered a “tumor suppressor gene.” This is legitimate cancer treatments, we do, indeed, need to consider rather narrow, respecting the ancient origin and very highly con- these details. One potential over-simplification: I’m using the served nature of the NF1 alphabetical code, and the intuitive un- word, “Ras,” generically, essentially ignoring ultimately relevant derstanding that the vast majority of eukaryotic species are not at differences between the several types of Ras, including those risk for tumors or cancer.
well-known – H-Ras, K-Ras, N-Ras – and the more esoteric ones – M-Ras, S-Ras, S2-Ras.
However, with the advent and ready availability of ge- nomic analyses now being exploited to understand the nature of Ras is docked at the PM, anticipating the extracellular normal and abnormal primitive organisms, such as amoebae, Nfn triggers that impinge on the PM, ordinarily at specific effector has been identified as a very important contributor to ordinary receptors (e.g., the epidermal growth factor receptor, (EGFR)). cell biology, particularly as relates to nutrition and feeding. For- As a naked, unadorned protein, Ras has no biological impact. In tunately, with the basic science work from the United Kingdom1 its active state, Ras is coupled to guanine triphosphate (GTP). and Southern California2 and elsewhere, a more realistic picture When the GTP γ-phosphate has been removed/transferred, 3 1 of the NF1 supergene3 is coming to light. Bloomfield et al1 and Ras is thereby coupled with guanine diphosphate (GDP). The Zhang et al2 have made it unequivocally clear that both the wild- dephosphorylation can be accounted for by Ras’ weak intrinsic type and mutant alleles at the NF1 locus in amoeba – Dictyostelium phosphatase (GTPase) catalysis, or by an extrinsic GTPase acti- specifically – do something to the organism’s anatomic engage- vating protein (GAP), ordinarily either the p120GAP or Nfn. Ras ment with the rest of the world, that is, it’s PM. Whether and how can then be reactivated by replacing the GDP with GTP via the the organism lives depends on what its NF1 gene does to its PM. guanine exchange factor (GEF). Attached to the PM, Ras, wheth- This is a far cry from the NF1 gene being exclusively a safeguard er as the tri- or di-nucleotide is consistently attached to GEF and against cancer. The activity of Nfn is not merely apparent at the occasionally attached to Nfn. I will refer to the triplet agglomera- PM. The activity of Nfn is a key determinant of the nature and tions as GRTN (GEF-RasGTP-Nfn) or GRDN (GEF-RasGDP- function of the PM. This fact is likely to be relevant to therapeu- Nfn).
tic strategies for NF1: attention to the gene’s raison d’être would seem to be important.
How the PM-bound GEF-RasGTP pair is joined with Nfn to create the GRTN triplet involves yet another substance, cc Copyright 2020 by Riccardi VM. This is an open-access article distributed under Creative Commons Attribution 4.0 International License (CC BY 4.0), which allows to copy, redistribute, remix, transform, and reproduce in any medium or format, even commercially, provided the original work is properly cited. Cancer Stud Mol Med Open J. 2020; 6(1): e1-e3. doi: 10.17140/CSMMOJ-6-e008 SPRED. (There are actually four SPRED moieties, numbered 1, Thus, the primary concern is not on the indirect down- 2, 3 or 4. For simplicity, I will use SPRED1, coded for by the stream adverse effects on the PM, but the direct and immediate SPRED1 gene, which, when mutated, gives rise to the Legius influences of mutant Nfn on the definitive elements of the func- syndrome.) Wildtype SPRED1 is responsible for transporting cy- tioning PM, much as is seen in Dictyostelium.1 Such immediate and C tosolic Nfn (NfnC) to the PM, and affording its attachment to direct adverse effects as an element of the PM might be manifest PM RasGTP, completing the triplet GRTN, that is, GRTNPM. Once in aberrant chemotaxis, cell migration and phagocytosis. In addi- this triplet is formed, SPRED molecules do not ordinarily con- tion, other membrane systems might be involved, including, for PM tribute to GRTNPM dynamics, at least in terms of Raf activation, example, those involved in melanosome formation and placement. PM although we still have a lot to learn about GRTNPM control of PM The intracellular and extracellular macromelanosomes that are part 11-13 dynamics themselves.
of NF1 café-au-lait spots (CLS) may be a useful in vitro model for pursuing this line of reasoning. Moreover, it is tempting to con- Ci Inactive cytosolic Raf (RafCi) occupies the vicinity near sider that abnormal NF1 SC PM functioning might account for PM Ci PM-attached GRTN: GRTNPM+RafCi. The two moieties become the initial abnormal SC behaviors after disruption of the axon/ Ci biochemically associated, and inactive Raf (RafCi) is thereby af- SC relationship.
PMi PM PMi fixed to the PM (Raf ): GRTN +Raf . This PM fixation pro- PM PMi cess does not activate Raf. Next, the GRTN and Raf dis-