Matrix Remodeling Associated Genes (MXRAs): structural diversity, functional significance, and therapeutic potential in tumor microenvironments

Abstract

The Matrix Remodeling Associated Genes (MXRAs) family, comprising eight distinct members (MXRA1-8), plays a crucial role in the development and maintenance of higher vertebrate cells. These proteins are primarily involved in the regulation of intercellular adhesion and the remodeling of the extracellular matrix (ECM). Recent investigations have highlighted the significant roles of MXRAs in the modulation of tumor growth and progression, establishing them as vital components in the oncogenic landscape. Notably, each MXRA member exhibits unique structural characteristics and functional properties, contributing to a diverse array of regulatory effects within the tumor context. This review seeks to provide a comprehensive analysis of the structural attributes, functional contributions, and activities of MXRAs within the tumor microenvironment. By elucidating the underlying mechanisms of action, this paper aims to offer novel insights and strategic approaches for the identification of early diagnostic biomarkers, as well as potential therapeutic targets that may facilitate molecular interventions aimed at inhibiting tumor development.

Keywords: Cell adhesion; MXRAs; Matrix remodeling; Tumor.

Fig. 1

The domain diagram of MXRAs. MXRA1 features a C-terminal PDZ-binding motif (PBM) and calmodulin-binding domain (CBD); MXRA2 possesses C-terminal tandem atypical calmodulin-homologous domains (CH1/CH2) and an N-terminal region with cyclin B1/Cdc2 phosphorylation sites, a tyrosine phosphorylation site, and PKC/CK2 phosphorylation sequences; MXRA3 contains a unique N-terminal KN motif and KANK, with a C-terminal region including ANKs and a coiled-coil domain; MXRA4 is structurally organized from N- to C-terminus with CTLD (D1), EGF-like domains (D2), a mucin-like domain (D3), a transmembrane domain (D4), a cytoplasmic domain (D5), and a domain DX; MXRA5 contains leucine-rich repeats (LRRs) and immunoglobulin-like C2-type domains for protein interactions and recognition; MXRA6 is composed of an N-terminal ABD I region (protein tyrosine phosphatase/C2), a central ABD II region, and a C-terminal region (SH2/PTB domains); MXRA7 is an ECM component with incompletely understood structure and function; and MXRA8 features an extracellular domain of double N-terminal V-type Ig-like domains, a transmembrane domain, and a short cytoplasmic domain

Fig. 2

Biological function of MXRAs. MXRA1, through its C-terminal PDZ-binding motif (PBM) that interacts with proteins like nNOS, CASK, Homer 1, PISP, and PDLIM1 to modulate calcium signaling, and its calmodulin-binding domain (CBD) that regulates calcium ion activity via calmodulin interaction, maintains intracellular and extracellular calcium homeostasis, inhibits the Calcineurin (CaN)/nuclear factor of activated T cells (NFAT) pathway (downregulating RCAN1.4 and COX-2 to impair angiogenesis); MXRA2, through its C-terminal CH2 domain that binds integrin-linked kinase (ILK) to activate integrin signaling, remodel the actin cytoskeleton, and modulate cell adhesion/migration (via a conserved paxillin-binding subdomain (PBS) interacting with paxillin’s LD motif to connect integrins and ECM, an absence of the C-terminal fragment impairs MXRA2 function); and its N-terminal region containing cyclin B1/Cdc2 phosphorylation sites, a tyrosine phosphorylation site, and PKC/casein kinase II phosphorylation sequences activated by the ERK pathway to regulate Rho family signaling and cell spreading/movement/migration (inhibited by MEK1 inhibition via UO126), directly interacts with Rac (deficiency augmenting Rac activation and lamellipodia formation) and activates Src or promotes phosphorylation of p21-activated kinase (PAK) and p38 MAPK to degrade ECM and initiate metastasis; MXRA3 modulates cell migration by forming an MXRA3-talin complex (KN motif-mediated interaction with talin’s R7 domain) that is recruited to adhesion plaques (β-integrins) to induce structural modifications and competitively inhibit integrin-actomyosin interactions (reducing adhesion strength/traction), recognizes KIF21A (ANK domains) to inhibit microtubule growth and influence cell transport/cytoskeleton maintenance/cellular development, regulates Rho GTPase activity (reducing podocyte migration by increasing GTP-bound RhoA), inhibits NF-κB p65 while enhancing VEGF/bFGF expression to benefit myocardial infarction, suppresses inflammation in a Parkinson’s disease astrocyte model (reducing TNF-α/IL-1β secretion, decreasing oxidative stress, and enhancing antioxidant enzyme activity), and attenuates apoptosis in sepsis-related acute lung injury by interacting with HSP70 to inhibit AIF release. MXRA4, existing in soluble form (secreted by HUVECs as a serum complement C1q receptor) and membrane-bound form, exhibits pro-angiogenic capabilities by forming complexes with MMRN2 or IGFBP7 to activate VEGF-A/TGF-β2 signaling pathways and enhance tumor angiogenesis; MXRA5, activating the MAPK signaling pathway to promote cell proliferation and invasion in osteoarthritis cartilage/synovial fluid, appears to protect against kidney tissue injury by promoting an anti-inflammatory/anti-fibrotic response (linked to the TGF-β pathway by inhibiting chemokine/fibronectin expression to alleviate inflammation/fibrosis); MXRA6, with key functional SH2/PTB domains that bind tyrosine-phosphorylated proteins (PI3K, EGFR, FAK) to initiate PTK-mediated signaling for cell growth/polarization/migration and interact with integrin β subunits to modulate cell adhesion/migration/proliferation, regulates Rho GTPase activity by interacting with DLC1 to activate the Hippo signaling pathway (impacting cell proliferation/EMT/tumor progression), interacts with PP1α via the ABD I region to govern cell polarization/migration/invasion, and potentially influences cytoskeletal organization/membrane dynamics/intracellular signaling; MXRA7 modulates inflammatory responses (exacerbating liver injury by enhancing matrix remodeling genes FN1/TIMP1), and regulates other physiological processes (inhibiting corneal neovascularization/promoting skin wound healing); MXRA8, with its extracellular domain facilitating intercellular adhesion by interacting with integrin αvβ3 (directly impeding integrin αv/β3 heterodimerization, with genetic deletion upregulating osteoclast-related Ig-like receptors/integrin αvβ3 and negatively modulating osteoclast differentiation), suppresses integrin αvβ3/FAK signaling and inhibits angiogenesis upon overexpression in HUVECs, and functions as a key receptor for arthritis-causing alphaviruses by interacting with viral E2-E1 heterodimers to promote viral entry

Fig. 3

Expression of MXRAs in tumors. The blue arrow indicates down-regulation in tumor tissues, and the red arrow indicates up-regulation in tumor tissues. Tumor abbreviation: AML Acute myeloid leukemia, BLCA Bladder urothelial carcinoma, BRCA Breast invasive carcinoma, CRC Colorectal cancer, GBM Glioblastoma multiformeGBM, LIHC Liver hepatocellular carcinoma, LUAD Lung adenocarcinoma, MM Multiple myeloma, OV Ovarian serous cystadenocarcinoma, PAAD Pancreatic adenocarcinoma, PRAD Prostate adenocarcinoma, RCC Renal cell carcinoma, SKCM Skin cutaneous melanoma, STAD Stomach adenocarcinoma, THCA Thyroid carcinoma

Fig. 4

MXRAs is involved in chemotherapy resistance. MXRA2, by disrupting adhesion signaling in tumors, leads to chemotherapy drug resistance; conversely, MXRA3 downregulation increases chemotherapy drug sensitivity through altered microtubule dynamics. Furthermore, MXRA4 inhibition enhances drug delivery by normalizing tumor vessels, improving the response to chemotherapy drugs. In tumors, MXRA7 influences chemotherapy drug-induced apoptosis via the caspase pathway, while MXRA8 inhibition sensitizes tumor cells to chemotherapy drug treatment

Fig. 5

MXRAs are regulated by miRNA. MXRA1, MXRA4, MXRA5, and MXRA6 are negatively regulated by miR-4261, miR-92a-3p, miR-30b, and a group of miRNAs including miR-942, miR-152, miR-31-5p, and miR-548j, respectively