The myotubularin family of lipid phosphatases in disease and in spermatogenesis

Abstract

The MTM (myotubularin)/MTMR (myotubularin-related) protein family is comprised of 15 lipid phosphatases, of which nine members are catalytically active. MTMs are known to play a fundamental role in human physiology as gene mutations can give rise to X-linked myotubular myopathy or Charcot–Marie–Tooth disease, which manifest in skeletal muscle or in peripheral neurons respectively. Interestingly, studies have shown MTMR2 and MTMR5, two MTM family members, to be highly expressed in the testis, particularly in Sertoli and germ cells, and knockout of either gene resulted in spermatogenic defects. Other studies have shown that MTMR2 functions in endocytosis and membrane trafficking. In the testis, MTMR2 interacts and co-localizes with c-Src/phospho-Src-(Tyr416), a non-receptor protein tyrosine kinase that regulates the phosphorylation state of proteins at the apical ES (ectoplasmic specialization), a unique type of cell junction found between Sertoli cells and elongating/elongated spermatids. In the present review, we highlight recent findings that have made a significant impact on our understanding of this protein family in normal cell function and in disease, with the emphasis on the role of MTMs and MTMRs in spermatogenesis. We also describe a working model to explain how MTMR2 interacts with other proteins such as c-Src, dynamin 2, EPS8 (growth factor receptor pathway substrate 8) and ARP2/3 (actin-related protein 2/3) at the apical ES and the apical TBC (tubulobulbar complex; tubular-like invaginations that function in the disassembly of the apical ES and in the recycling of its components) to regulate spermiation at late stage VIII of the seminiferous epithelial cycle.

Actin-binding protein drebrin E is involved in junction dynamics during spermatogenesis

“…Drebrin has been implicated in the regulation of cell adhesion since it was demonstrated to stabilize connexin 43 (Cx43)-containing GJ plaques, possibly serving as an adaptor of the actin cytoskeleton 49 by recruiting or modulating the activity of other actin regulatory proteins, such as Esp8 and the Arp2/3 complex, which confer actin filament bundling and branching, respectively. 15,[50][51][52][53] Cx43 was shown recently to be involved in junction restructuring at the BTB, particularly in the reassembly of the TJ-barrier following its disruption, 38,54 which occurs during the transit of preleptotene spermatocytes at stage VIII of the epithelial cycle. Thus, it was tempting to speculate that drebrin E is participating in these events by recruiting actin regulatory proteins, such as Arp3 to the apical and/or the basal ES since Arp3 was shown to be a binding partner of drebrin E as demonstrated herein.…”

“…55 Recent studies have shown this site to be the apical ES where endocytic vesicle-mediated protein trafficking events begins at late stage VII of the epithelial cycle 56 so that "old" apical ES proteins (e.g., N-cadherin, nectins, JAM-A) can be endocytosed, transcytosed and recycled for assembly of the "new" apical ES that arises during spermiogenesis at the interface of Sertoli cell and step 8 spermatid. 1,33,53 These events are also necessary to confer spermatid polarity so that the heads of developing spermatids can point toward the basement membrane Figure 3 (See opposite page). Apical eS disruption induced by adjudin is accompanied by a considerable reduction of drebrin e at the apical eS, but not at the BtB.…”

A phosphoinositide conversion mechanism for exit from endosomes

“…The latter contributes to the maintenance of excitatory synapses by regulating endosomal trafficking of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors. Additionally to peripheral neuropathies, MTMR2-deficient mice suffer from defects in spermatogenesis (Mruk and Cheng 2011) due to impaired dynamics of adhesion junctions and defects in membrane trafficking. The different disease phenotypes upon loss of MTMR2 are closely linked to regulation of its catalytic activity and localization by either MTMR5 or MTMR13:…”

Defining the Protein-Protein Interaction Network of the Human Protein Tyrosine Phosphatase Family

“…Regulation-The MTM/MTMR DSP subfamily comprises 15 members: MTM1 and MTMRs 1-14 (7). Nine members of this family have been shown to have catalytic activity as both lipid phosphatases and PTPs (7).…”

“…Moreover, MTM-DSPs and their related DSPs (MTMR-DSPs) possess the conserved PTP domains but lack the residues that are critical for catalysis. However, not all components of this family are categorized as pseudophosphatases, because some of them have lipid phosphatase activity (7). Because the classic PTPs (rPTP and nrPTP), the atypical-MKP DSPs, and the MTM/MTMR-DSPs are the three largest subfamilies of human PTPs, we focused mostly on these three subfamilies for the analysis presented here.…”