8.A.74 The TM9 or Phg1 Targeting Receptor (Phg1) Family TM9 family proteins (also named Phg1 proteins) control cell adhesion by determining the cell surface localization of adhesion proteins such as the Dictyostelium SibA protein. Perrin et al. 2015 showed that the glycine-rich transmembrane segments (TMSs) of SibA are sufficient to confer Phg1A-dependent surface targeting to a reporter protein. In Dictyostelium phg1A- knockout (KO) cells, proteins with glycine-rich TMSs were less efficiently transported out of the endoplasmic reticulum (ER) to the cell surface. Phg1A, as well as its human ortholog TM9SF4 specifically associated with glycine-rich TMSs. In human cells, genetic inactivation of TM9SF4 resulted in an increased retention of glycine-rich TMSs in the endoplasmic reticulum, whereas TM9SF4 overexpression enhanced their surface localization. The bulk of the TM9SF4 protein was localized in the Golgi complex, and a proximity-ligation assay suggested that it might interact with glycine-rich TMSs. It thus appears that one of the main roles of TM9 proteins is to serve as intramembrane cargo receptors controlling exocytosis and surface localization of a subset of membrane proteins (Perrin et al. 2015).
References:
Arias-Aragón, F., E. Robles-Lanuza, &.#.1.9.3.;. Sánchez-Gómez, A. Martinez-Mir, and F.G. Scholl. (2025). Analysis of neurexin-neuroligin complexes supports an isoform-specific role for β-neurexin-1 dysfunction in a mouse model of autism. Mol Brain 18: 20.
Connor, S.A. and T.J. Siddiqui. (2023). Synapse organizers as molecular codes for synaptic plasticity. Trends Neurosci. [Epub: Ahead of Print]
Gery, S., D. Yin, D. Xie, K.L. Black, and H.P. Koeffler. (2003). TMEFF1 and brain tumors. Oncogene 22: 2723-2727.
Hudlikar, R.R., D. Sargsyan, W. Li, R. Wu, M. Zheng, and A.N. Kong. (2021). Epigenomic, Transcriptomic, and Protective Effect of Carotenoid Fucoxanthin in High Glucose-Induced Oxidative Stress in Mes13 Kidney Mesangial Cells. Chem Res Toxicol. [Epub: Ahead of Print]
Huzé, C., S. Bauché, P. Richard, F. Chevessier, E. Goillot, K. Gaudon, A. Ben Ammar, A. Chaboud, I. Grosjean, H.A. Lecuyer, V. Bernard, A. Rouche, N. Alexandri, T. Kuntzer, M. Fardeau, E. Fournier, A. Brancaccio, M.A. Rüegg, J. Koenig, B. Eymard, L. Schaeffer, and D. Hantaï. (2009). Identification of an agrin mutation that causes congenital myasthenia and affects synapse function. Am J Hum Genet 85: 155-167.
Koppel, N., M.B. Friese, H.L. Cardasis, T.A. Neubert, and S.J. Burden. (2019). Vezatin is required for the maturation of the neuromuscular synapse. Mol. Biol. Cell 30: 2571-2583.
Lee, S.J., T. Uemura, T. Yoshida, and M. Mishina. (2012). GluRδ2 assembles four neurexins into trans-synaptic triad to trigger synapse formation. J. Neurosci. 32: 4688-4701.
Lok, H.C. and J.B. Kwok. (2021). The Role of White Matter Dysfunction and Leukoencephalopathy/Leukodystrophy Genes in the Aetiology of Frontotemporal Dementias: Implications for Novel Approaches to Therapeutics. Int J Mol Sci 22:.
Matsuda, K. (2016). Synapse organization and modulation via C1q family proteins and their receptors in the central nervous system. Neurosci Res. [Epub: Ahead of Print]
Perrin, J., M. Le Coadic, A. Vernay, M. Dias, N. Gopaldass, H. Ouertatani-Sakouhi, and P. Cosson. (2015). TM9 family proteins control surface targeting of glycine-rich transmembrane domains. J Cell Sci 128: 2269-2277.
Vaags, A.K., A.C. Lionel, D. Sato, M. Goodenberger, Q.P. Stein, S. Curran, C. Ogilvie, J.W. Ahn, I. Drmic, L. Senman, C. Chrysler, A. Thompson, C. Russell, A. Prasad, S. Walker, D. Pinto, C.R. Marshall, D.J. Stavropoulos, L. Zwaigenbaum, B.A. Fernandez, E. Fombonne, P.F. Bolton, D.A. Collier, J.C. Hodge, W. Roberts, P. Szatmari, and S.W. Scherer. (2012). Rare deletions at the neurexin 3 locus in autism spectrum disorder. Am J Hum Genet 90: 133-141.
Wang, Z., Y. Tao, C. Song, P. Liu, C. Wang, Y. Li, W. Cui, K. Xie, L. Zhang, and G. Wang. (2020). Spinal hevin mediates membrane trafficking of GluA1-containing AMPA receptors in remifentanil-induced postoperative hyperalgesia in mice. Neurosci Lett 722: 134855.
Zhang, W., A.S. Coldefy, S.R. Hubbard, and S.J. Burden. (2011). Agrin binds to the N-terminal region of Lrp4 protein and stimulates association between Lrp4 and the first immunoglobulin-like domain in muscle-specific kinase (MuSK). J. Biol. Chem. 286: 40624-40630.
Zhao, Y., J. Yu, A. Huang, Q. Yang, G. Li, Y. Yang, and Y. Chen. (2023). ROS impairs tumor vasculature normalization through an endocytosis effect of caveolae on extracellular SPARC. Cancer Cell Int 23: 152.
Examples:
TC#	Name	Organismal Type	Example
8.A.74.1.1	Neurexin-2 of 1712 aas and 2 TMSs, N- and C-terminal. It is a neuronal cell surface protein that may be involved in cell recognition and cell adhesion. It may also mediate intracellular signaling. Comparisons with Neurexin 1 and 3 have been published, and they serve very different functions. Neurexins may play a role in autism in mice (Arias-Aragón et al. 2025). The three human neurexins are 63 - 70% identical.		Neurexin-2 of Homo sapiens

8.A.74.1.2	Neurexin-1 (NRX1) of 1477 aas and 2 TMSs, one N-terminal and one C-terminal. It is a cell surface protein involved in cell-cell-interactions, exocytosis of secretory granules and regulation of signal transmission including several transport systems. Neurexin function is isoform-specific. It is found in trans-synaptic tripartite complexes which consist of one unit of the cerebellin-1 (Cbln1) hexamer, four monomeric neurexins containing a splice site 4 insertion at presynaptic terminals and the postsynaptic GluD2 dimers (Matsuda 2016). The trans-synaptic interaction of postsynaptic glutamate receptor δ2 (GluRδ2, an orthologue of TC#1.A.10.1.8) and presynaptic neurexins through cerebellin precursor protein 1 (Cbln1) mediates synapse formation in vivo in the cerebellum (Lee et al. 2012). Members of the neurexin family appear to be homologous to domains in some members of TC family 9.B.87. Neurexin-1-β (NRX1B; P58400; 472 aas with 2 TMSs, N- and C-terminal) is a neuronal cell surface protein involved in cell recognition and cell adhesion by forming intracellular junctions through binding to neuroligins. Plays a role in formation of synaptic junctions. It is a synapse organizer that provides molecular codes for synaptic plasticity (Connor and Siddiqui 2023). Major brain disorders emerge when the functions of these proteins are compromised. There are several families of these organizers that govern synapses. They are diverse, but converge on the structure, function, and plasticity of synapses (Connor and Siddiqui 2023).		Neurexin-1 of Homo sapiens

8.A.74.1.3	Agrin (GRN) of 2068 aas and 1 or 2 TMSs, is a heparan sulfate basal lamina glycoprotein that plays a central role in the formation and the maintenance of neuromuscular junctions (NMJs) and directs key events in postsynaptic differentiation. It is a component of the AGRN-LRP4 receptor complex that induces the phosphorylation and activation of MUSK. The activation of MUSK in myotubes induces the formation of NMJs by regulating different processes including the transcription of specific genes and the clustering of AChR in the postsynaptic membrane, the latter which requires calcium ions for clustering (Huzé et al. 2009; Zhang et al. 2011). Agrin, Lrp4, and MuSK, are required for the initial formation, subsequent maturation, and long-term stabilization of mammalian neuromuscular synapses (Koppel et al. 2019). It maky play a role in frontotemporal dementia (FTD) (Lok and Kwok 2021).		Agrin of Homo sapiens

8.A.74.1.4	Tomoregulin-1 or transmembrane protein with EGF-like and two follistatin-like domains 1 (TMEFF1) of 270 aas and 2 TMSs, one N-terminal and the other C-terminal. It may inhibit NODAL and BMP signaling during neural patterning, and may also be a tumor suppressor in brain cancers (Gery et al. 2003). It may modulate ion channel transport and glucose metabolism (Hudlikar et al. 2021).		TMEFF1 of Homo sapiens

8.A.74.1.5	Hevin or Sparc-like protein 1, SPARCL1, also called Proliferation-inducing protein, PIG33, of 664 aas and one N-terminal TMS. It regulates Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs). It is a matricellular protein involved in tissue repair and remodeling, and is crucial for initiation and development of excitatory synapses. Specifically, it is important for the AMPA receptor and its mediation of fast synaptic transmission in the central nervous system (CNS) (Wang et al. 2020). Thus, spinal Hevin is involved in the maintenance of remifentanil-induced postoperative hyperalgesia via modulating membrane trafficking of AMPA receptors (Wang et al. 2020).		Hevin of Homo sapiens

8.A.74.1.6	SPARC, with 303 aas and 1 N-terminal TMS. It may regulate cell growth through interactions with the extracellular matrix and cytokines. It binds calcium and copper, several types of collagen, albumin, thrombospondin, PDGF and cell membranes. There are two calcium binding sites; an acidic domain that binds 5 to 8 Ca²⁺ with a low affinity and an EF-hand loop that binds a Ca²⁺ ion with a high affinity. In an oxidative stress environment, neovascularization within a tumor occurs with structural deterioration and decreased perfusion capacity. One of the main regulatory mechanisms is the migration of extracellular SPARC from the endothelium to intracellular compartments via Caveolin-1 carriers (Zhao et al. 2023).		SPARC of Homo sapiens

8.A.74.1.7	*Neurexin-3 (NRX2A) of 1643 aas and 2 TMSs, N- and C-terminal. It may play a role in autism (Vaags et al.* 2012).**		NRX2A of Homo sapiens