The nine-transmembrane superfamily proteins (TM9SFs) consist of multiple members. Structurally, TM9SFs all contain a large extracellular domain and nine transmembrane domains, exhibiting high conservation and broad expression during evolution. Although functional studies on this protein family are currently limited, according to existing research, its members are closely associated with various biological functions such as cellular immunity, infection, autophagy, tumor invasion, and prognosis.
Related Products
Introduction of TM9SF
The TM9SF structure generally consists of a large non-cytosolic region (variable extracellular N-terminal domain) and nine transmembrane domains, which are highly conserved throughout evolution. The expression of this protein family is observed in various species such as bacteria, yeast, fruit flies, plants, and mammals, indicating its potentially significant biological role due to its high conservation during evolution.
Dictyostelium discoideum (D. discoideum), commonly known as slime mold, belongs to the phylum Amoebozoa in the kingdom of Fungi. Its morphology resembles that of the amoeba, a protozoan, and shares many similarities with mammalian cells in behavior, structure, and signaling pathways. When synthesizing proteins, it exhibits post-translational modification functions similar to eukaryotes. The D. discoideum genome contains at least three different genes encoding TM9 proteins: Phg1a, Phg1b, and Phg1c. In 2000, researchers used reverse genetics methods to study D. discoideum and discovered for the first time that TM9SF plays a crucial role in regulating cell adhesion and phagocytosis by modulating cell surface adhesion molecules. Combining the structural characteristics of TM9SF with its regulation of adhesion and phagocytic functions, it is speculated that the variable extracellular domain of TM9SF imparts different receptor specificities, while the conserved transmembrane domains establish connections with intracellular signaling mechanisms.
Currently, four TM9SF members (TM9SF1~TM9SF4) have been identified in mammals. TM9SF2 and TM9SF4 belong to the TM9SF II subgroup, along with the D. discoideum Phg1a, while TM9SF1 and TM9SF3 belong to subgroup I along with Phg1b.
Despite being discovered for some time, functional studies on the TM9SF protein family are relatively limited. However, existing research suggests that TM9SF is closely associated with various biological functions such as cellular immunity, infection, autophagy, tumor invasion, and prognosis.
Expression and Function of TM9SF1
TM9SF1, also known as MP70, was first cloned in 1997. It is one of the members of the transmembrane 9 superfamily, with broad expression in human tissues (especially in the lung, kidney, and pancreas) and various cell lines. Human TM9SF1 protein shares approximately 30% homology with its yeast counterpart, suggesting its possible involvement in certain ancient and important biological functions. Currently, most research on TM9SF1 focuses on its expression, with most studies suggesting that it primarily acts as a pro-autophagic gene.
Vascular Function
Researchers have discovered through proteomic methods that TM9SF1 is highly expressed in the ruptured vascular walls of intracranial aneurysms. Subsequent histological validation suggested that sustained high expression of TM9SF1 may be involved in the inflammatory and vascular wall protein degradation processes related to the formation and rupture of intracranial aneurysms. Interfering with endogenous TM9SF1 expression using siRNA can suppress the expression of inflammation-related genes (IL1β, IL8) and angiotensin-converting enzyme 1 (ACE1) in human umbilical vein endothelial cells.
Autophagy
Research has shown that TM9SF1 can induce autophagy in cervical cancer HeLa cell lines, although the related molecular mechanisms were not elucidated. Epigallocatechin-3-gallate (EGCG) can improve the recovery of skeletal muscle fiber atrophy induced by hindlimb suspension (HS) in rats, and its mechanism of action is related to the induction of autophagy and the upregulation of autophagy-related gene TM9SF1. Lithium can increase the survival rate of cultured corneal endothelial cells (CECs) against endoplasmic reticulum and oxidative stress, a function associated with the upregulation of the autophagy-related gene TM9SF1. In addition, M9SF1 inhibits the growth of 293T cells by inducing autophagy and endoplasmic reticulum stress.
Intracellular Transport
Research has shown that TM9SF1 is mainly located in the Golgi complex, where it can bind to transmembrane domains rich in glycine residues (TMDs) without altering the distribution ratio of the corresponding proteins on the endoplasmic reticulum and Golgi complexes, suggesting its potential role in mediating the transport of corresponding proteins between other organelles.
Tumors
Researchers analyzed selective alternative splicing (AS) events in 253 cervical cancer patients and found that exon skipping (ES) is the main AS event in cervical cancer patients. They also found that a gene may exhibit several different types of AS events, which may be related to the prognosis of cervical cancer. Further research revealed that TM9SF1 is associated with the survival and recurrence of cervical cancer and can serve as a prognostic marker for cervical cancer. Estrogen receptor-binding fragment-associated antigen 9 (EBAG9) is a tumor biomarker that exerts immunosuppressive effects, facilitating tumor progression and immune evasion. Miyazaki et al. confirmed in a spontaneous prostate cancer mouse model that TM9SF1 is a synergistic factor of EBAG9, regulating epithelial-mesenchymal transition (EMT) in cancer cells. Zaravinos et al. used gene chip analysis to find that TM9SF1 is a differentially expressed gene in bladder cancer tissues, suggesting its involvement in the occurrence and development of bladder cancer.
Expression and Function of TM9SF2
In recent years, research on the second member of the transmembrane 9 superfamily, TM9SF2, has been increasing, and its functions are gradually being revealed.
Embryonic Development
Researchers used differential display reverse transcriptase-polymerase chain reaction (DD RT-PCR) to discover that TM9SF2 is involved in the regulation of adult-repopulating hematopoietic stem cells (HSCs) and exhibits significant differential expression during the development of the aorta-gonad-mesonephros region, possibly related to embryonic development.
Infection
Infection studies revealed TM9SF2's critical role in chikungunya virus (CHIKV) and enterohemorrhagic Escherichia coli infections. TM9SF2 facilitates CHIKV infection by regulating heparan sulfate (HS) sulfation via NDST1. TM9SF2 mutations hinder EHCC virulence factors, reducing toxicity. TM9SF2, essential for Golgi function, affects Stx and ricin toxicity by modulating Gb3 synthesis and intracellular transport. TM9SF2's deletion alters Gb3 synthase localization, diminishing Stx toxicity. TM9SF2 emerges as a key host factor in pathogen infections, potentially through HS regulation.
Tumors
Furthermore, TM9SF2 also has a significant impact on the occurrence and development of tumors. Through mouse transposon mutagenesis screening found that TM9SF2 is a new colorectal cancer gene. High expression of TM9SF2 is associated with tumor staging, while low expression of TM9SF2 is associated with recurrence-free survival. Knocking out TM9SF2 can significantly reduce tumor adaptability. Long intergenic non-protein coding RNA 1232 (LINC01232) promotes pancreatic cancer cell proliferation and progression by regulating TM9SF2: LINC01232 is transcriptionally activated by SP1, upregulated in pancreatic cancer tissues, and associated with poor prognosis. It enhances the stability of TM9SF2 mRNA by recruiting eukaryotic translation initiation factor 4A3 (EIF4A3), thereby upregulating TM9SF2 expression to promote pancreatic cancer.
Expression and Function of TM9SF3
Research on TM9SF3 indicates its high expression in various tumor tissues, playing a role in tumor promotion.
Organelle Marker Molecules
A study revealed that the protein TM9SF3 is highly expressed in the Golgi apparatus of various cells, possibly serving as a new marker for this organelle. Another research identified TM9SF3 as a protein related to insulin secretory granules in pancreatic β cells, indicating its potential as a marker for these specific organelles.
Tumors
In breast cancer cell lines, the combination of SAHA and paclitaxel led to increased expression of TM9SF3, suggesting its role as a potential biomarker for treatment outcomes. TM9SF3 was also found to be upregulated in gastric cancer, particularly in aggressive forms, with implications for tumor invasion and prognosis. Further studies linked TM9SF3 to T-cell leukemia, showing its promotion of cell proliferation and invasion. Additionally, TM9SF3 is considered a potential molecular target for drug therapy against tumors.
Expression and Function of TM9SF4
TM9SF4 plays a significant role in immunology and oncology.
Cellular Immunity
Initially identified for its role in mediating the adhesion and engulfment of Yersinia pseudotuberculosis, TM9SF4 plays a crucial role in innate immune responses in Drosophila. Research indicates its involvement in cell adhesion and phagocytosis, particularly affecting the uptake of Gram-negative bacteria by fruit fly macrophages. Further investigations revealed its interaction with peptidoglycan recognition protein-LC (PGRP-LC), modulating its localization and signaling in Drosophila S2 cells. TM9SF4's function appears to uniquely integrate cytoskeleton network signals with bacterial recognition, facilitating the internalization of Gram-negative bacteria.
Intracellular Transport
TM9SF4 facilitates the migration of proteins containing specific transmembrane domains (TMDs) from the endoplasmic reticulum to the Golgi complex. Its interaction with TMDs rich in glycine, arginine, or aspartic acid residues underscores its role in intracellular protein trafficking.
Tumors
High TM9SF4 expression is observed in metastatic malignant melanoma, correlating with tumor aggressiveness. It localizes mainly in acidic vesicles of melanoma cells, where it interacts with early endosome antigens. Silencing TM9SF4 inhibits tumor metastasis, suggesting its potential as a therapeutic target. Moreover, TM9SF4 is implicated in regulating tumor pH changes by interacting with V-ATPase, affecting drug resistance and invasiveness of colon cancer cells. In breast cancer, TM9SF4 alleviates endoplasmic reticulum stress, promoting cell survival in drug-resistant cells. Inhibition of TM9SF4 expression enhances chemotherapy sensitivity, offering potential avenues for combating drug resistance in cancer therapy.
References
- Miyazaki T., et al. Extracellular vesicle-mediated EBAG9 transfer from cancer cells to tumor microenvironment promotes immune escape and tumor progression. Oncogenesis. 2018, 7: 7.
- Zaravinos A., et al. Identification of common differentially expressed genes in urinary bladder cancer. PLoS One. 2011, 6: e18135
.
