Crucial Roles of Ez-Metastasizing in Ezrin in Metastasis

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1		Rand Gabriel M. Buenaventura	--	4184	2023-06-22 16:13:04	\|
2	Reference format revised.	Lindsay Dong	-2 word(s)	4182	2023-06-25 03:31:53	\|

This entry is adapted from the peer-reviewed paper 10.3390/cells12121620

Ezrin is the cytoskeletal organizer and functions in the modulation of membrane–cytoskeleton interaction, maintenance of cell shape and structure, and regulation of cell–cell adhesion and movement, as well as cell survival. Ezrin plays a critical role in regulating tumor metastasis through interaction with other binding proteins. Notably, Ezrin has been reported to interact with immune cells, allowing tumor cells to escape immune attack in metastasis.

Ezrin binding protein cell migration tumor metastasis

1. Introduction

In 1983, Ezrin was discovered and initially characterized as a small element of the microvilli at chicken intestinal epithelial cell brush borders ^[1]. In later studies investigating similar proteins in actin-based cytoskeleton structures, proteins such as cytovillin ^[2]^[3], p81 ^[4], and 80K ^[5]^[6] were all identified and subsequently established as the same protein ^[7]^[8]^[9]^[10]^[11]. In the coming years, Ezrin was shown to be a key player in linking the plasma membrane to the cytoskeleton ^[12]. It has been well documented that Ezrin participates in various cellular processes such as signal transduction ^[13], cell proliferation ^[14], cell–cell adhesion ^[15]^[16], membrane projections ^[17]^[18]^[19], and cell motility ^[20]^[21], among others.

Ezrin, part of the ezrin/radixin/moesin (ERM) family of proteins, is encoded by the EZR gene. Ezrin contains three major domains: the amino-terminal FERM (four-point one, Ezrin, Radixin, Moesin) domain, the α-helical domain, and the carboxy-terminal ERM association domain (C-ERMAD) ^[22]^[23]. The FERM domain comprises three subdomains, F1, F2, and F3, and binds with cell membrane lipids, transmembrane proteins, and other membrane-associated proteins. The C-ERMAD domain contains a binding site interconnecting with filamentous actin (F-actin). A linker region rich in proline lies between the α-helical and C-ERMAD domains ^[24] (Figure 1).

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Figure 1. Ezrin is a linker between the cytoskeleton and cell membranes. (A) Schematic of the Ezrin protein. Ezrin is a protein with 586 amino acids and consists of FERM, α-helical and c-ERMAD domains, and a linker region. (B) Ezrin interconverts from an inactive closed conformation to an active open conformation dynamically. When Ezrin is recruited to the plasma membrane and binds to PIP₂ at its FERM domain, c-ERMAD is released, allowing kinases such as Rho or PKC to phosphorylate the c terminal at Thr567, thereby converting Ezrin to the active form capable of binding to actin.

Like other ERM proteins, Ezrin can rapidly interconvert from an inactive closed to an active open conformation. In its closed conformation, Ezrin is localized in the cytoplasm where the FERM and C-ERMAD domains bind to each other, masking the F-actin and membrane-binding sites ^[25]. Ezrin becomes activated through a two-step process ^[26]. In the first step, Ezrin is recruited to the plasma membrane regions rich in phosphatidylinositol 4,5-bisphosphate (PIP₂), where PIP₂ binds to the FERM domain and exposes the conserved C-terminal threonine residue (Thr567). At the second step, several kinases (e.g., Rho Kinase, PKCα, PKCθ, NIK, Mst4 and LOK) can phosphorylate the Thr567 of Ezrin, causing Ezrin’s intramolecular head-to-tail interaction to be disrupted and Ezrin to subsequently become activated. Phosphorylated Ezrin is now able to bind to membrane-associated proteins and the actin cytoskeleton, acting as a membrane–cytoskeleton linker ^[12] (Figure 1B).

2. Ezrin as a Linker between the Plasma Membrane and Cytoskeleton

2.1. Modulation of Membrane–Cytoskeleton Interactions

MCIs are necessary interactions between the plasma membrane and underlying actin cytoskeleton to communicate changes in the outside environment, serving as a hub for transmitting extracellular signals into the cell ^[27]. As a scaffold, Ezrin regulates several signal transduction pathways, such as PI3K signaling, Hepatocyte Growth Factor (HGF)/Met signaling, and RhoA signaling, impacting physiological function ^[20]^[28]^[29]^[30]. Ezrin is critical for survival as Ezrin-deficient mice were found to only survive 1.5 weeks after birth due to an intestinal defect preventing nutrient absorption ^[31]^[32].

Ezrin’s interactions with various proteins can modulate membrane–cytoskeleton interactions and result in differing outcomes. When activated by RhoA/ROCK1, Ezrin binds to Orai1 (oral calcium release-activated calcium modulator 1) to inhibit calcium entry in retracting blebs, resulting in a decrease in cytoplasmic calcium while also triggering the rapid assembly of the actin cortex ^[33]. While Ezrin is acetylated by lysine acetyltransferase PCAF (p300/CBP-associated factor), this prevents the phosphorylation of Ezrin at Thr567 and induces the translocation of Ezrin to the cytoplasm from the plasma membrane, promoting MDA-MB-231 breast cancer cell motility during migration and invasion ^[34]. When PRL3 (phosphatase of regenerating liver 3) dephosphorylates Ezrin at Thr567, this can initiate protrusion formation, inducing lamellipodia formation in osteosarcoma U2OS cells ^[35].

2.2. Maintenance of Cell Shape and Cell Structure

Ezrin maintains cell shape and structure. Several studies have demonstrated that Ezrin is important in maintaining a cell surface’s topography and associates with many cell surface structures on various cell types ^[17]^[36]^[37]. Ezrin deficiency in mice resulted in drastic changes in the morphology of microvilli, which become malformed and shortened ^[31]^[38].

Furthermore, Ezrin’s role as a crosslinker between the cortical actin network and the plasma membrane can affect membrane tension. In zebrafish mesodermal cells, researchers used either a nonphosphorylatable form of Ezrin or morpholinos that inactivated ERM protein function and found that membrane tension, adhesion energy, and dynamic tether force were significantly reduced in affected cells ^[39]. In contrast, modified super-active Ezrin expression in transgenic mice increased the membrane tension to 70% ^[40]. Later research found that modified plasma membrane interactions were associated with the reduced effectiveness of Ezrin ^[41].

2.3. Regulation of Cell–Cell Adhesion

Ezrin is also involved in the regulation of cell–cell adhesion. When Ezrin and other ERM proteins are suppressed, cell–matrix and cell adhesion are hampered in mouse epithelial cells ^[42]. In fact, Ezrin binds to cell adhesion proteins, e.g., CD44, CD43, intracellular adhesion molecule (ICAM)-1 and 2, and L-selectin, at the juxtamembrane amino acid sequences ^[15]^[43]^[44]^[45]^[46]. Therefore, directly crosslinking these cell adhesion proteins to actin filaments, such as when tethering CD44 to the cytoskeleton in macrophages, CD44 functions as a picket that forms a barrier to Fc receptor engagement in the plasma membrane ^[47].

2.4. Regulation of Cell Movement

Ezrin regulates cell movement, thereby affecting cell motility and migration. HGF can induce the dissociation, migration, and remodeling of epithelial monolayers by modifying cell–cell adhesion and the actin cytoskeleton ^[20]. Crepaldi et al. found that Ezrin is crucial to this HGF-mediated morphogenesis in LLC-PK1 cells. When Ezrin is overproduced in LLC-PK1 cells, cell migration and tubulogenesis are enhanced. When a truncated variant of Ezrin is introduced, the morphogenic and mitogenic response to HGF is impaired instead. Protein kinase C (PKC) has been implicated in the promotion of cell migratory phenotypes ^[48], and when overexpressed in MCF-10A human breast cells, cell motility is enhanced ^[49]. This PKC-driven migratory response is directly correlated with Thr567 phosphorylation of Ezrin, and PKCα can form a molecular complex with Ezrin and hyperphosphorylate it at Thr567 ^[21].

3. Ezrin Interacts with Metastasis-Related Proteins

3.1. ACTB

β-actin, encoded by the ACTB gene, is a cytoskeletal structural protein involved in cell growth, migration, and metastasis ^[50]^[51]. Ezrin interacts specifically with β-actin filaments and colocalizes within distal reaches of forward protrusions ^[52].

3.2. ADORA2B

ADORA2B encodes a G-protein-coupled adenosine receptor adenosine A2b receptor (A2bR), which can induce cAMP production ^[53]. Its overexpression has been correlated with tumor progression, which is important in immunosuppressive activity, tumor angiogenesis, and metastasis ^[54]. Upon agonist stimulation, A2bR is recruited to the plasma membrane, where it interacts with Ezrin, NHERF2, and PKA ^[55]. This interaction helps anchor A2bR to the plasma membrane and stabilize the receptor.

3.3. ADRA1B

ADRA1B encodes α1B-adrenergic receptor (α1B-AR), which is a G-protein-coupled receptor that activates mitogenic responses and regulates cell growth and proliferation in many cells. When α1B-AR is overexpressed and activated, it can induce neoplastic transformation and function as an oncogene ^[56]. Ezrin directly interacts with α1B-AR through a polyarginine motif on the receptor’s C-tail ^[57], regulating α1B-AR recycling to the plasma membrane, implying that Ezrin has a broader role in GPCR trafficking to promote tumor progression.

3.4. ARF6

ADP-ribosylation factor 6 (Arf6) is a member of the ADP-ribosylation factor family of small GTPases. Arf6 mainly functions at the plasma membrane, regulating endocytic pathways, protein trafficking and recycling, and actin remodeling at the leading edge of migrating cells ^[58]. A GDP-locked mutant of Arf6 (Arf6-T44N) has been found to localize with Ezrin in actin- and PIP₂-enriched regions, suggesting that the Arf6 GDP-GTP cycle occurs at the plasma membrane ^[59]. Arf6 function is primarily dictated by the lifetime of its GTP-bound active form, which is orchestrated by the Arf6-specific GTPase-activating protein, ACAP4.

3.5. ARHGDIA

ARHGDIA encodes the protein of Rho guanine nucleotide dissociation inhibitory factors 1 (RhoGDI1). Part of the family of Rho GDP-Dissociation Inhibitors (Rho-GDIs), RhoGDI1 is an inhibitory regulator that forms a complex with the GDP-bound inactive form of Rho-GTPases, thereby inhibiting their activation ^[60]. Ezrin and Rho-GDIs directly interact at the FERM domain, which initiates the activation of Rho GTPases by reducing Rho-GDI activity and rescuing Rho GTPase from the Rho-GDP/GDI complex ^[61]. The interaction between Rho-GDIs and Ezrin can regulate the reorganization of actin filaments to drive cell shape, motility, and migration ^[60]^[62].

3.6. ARHGDIB

ARHGDIB encodes Rho guanine nucleotide dissociation inhibitory factors 2 (RhoGDI2), also known as LyGDI. Another member of the Rho-GDIs, LyGDI was found to function in cancer metastasis by anchoring Rho proteins to the cell membrane ^[63]. The expression of a C-terminal-truncated form of LyGDI (ΔC-LyGDI) induced pulmonary metastasis in 1-1ras1000 cells; in contrast, full-length LyGDI did not induce metastasis.

3.7. CD44

CD44 (the cluster of differentiation 44) is a cell-surface glycoprotein involved in cell–cell interactions and cell adhesion and migration. Ezrin is an intracellular anchor to CD44, linking it to the cytoskeleton ^[64]. CD44 binds directly to the FERM domain of Ezrin, and this interaction is regulated by Rho and PIP₂ ^[44]. A recent study found that the binding efficiency of CD44 and FERM is directly impacted by a PIP2-dependent conformational switching of phosphorylated CD44 ^[65]. CD44 has been shown to promote tumor growth and invasiveness by recruiting Ezrin to its cytoplasmic tail and thus producing links to the cytoskeleton ^[66].

3.8. CDH1

CDH1 encodes E-cadherin, also known as Cadherin-1 or CD324. E-cadherin plays a major role in epithelial cell–cell adhesion. E-cadherin loss of function is associated with the disaggregation of tumor cells, thereby promoting their invasive and metastatic potential ^[67]. Ezrin interacts with E-cadherin to regulate cell–cell and cell–matrix adhesion, therefore controlling tumor cell adhesion and invasiveness ^[68].

3.9. CLIC5

Chloride intracellular channel 5 (CLIC5) is a protein encoded by the CLIC5 gene. CLIC5 was initially discovered as part of a protein complex from extracts of human placental microvilli alongside several actin-associated proteins such as Ezrin ^[69]. In renal glomerular podocytes, CLIC5 localizes to the apical plasma membrane of foot processes as a component of the Ezrin/NHERF2/podocalyxin complex and is required for podocyte structure and function. Deficient CLIC5 in mice markedly reduced Ezrin levels and increased susceptibility to glomerular injury, highlighting the importance of CLIC5 and Ezrin in podocyte integrity ^[70]^[71].

3.10. CTNNB1

CTNNB1 encodes β-catenin, which regulates cell–cell adhesion and gene transcription. Like E-cadherin, Ezrin can regulate cell–cell and cell–matrix adhesion by interacting with β-catenin ^[68]. Part of the Wnt/β-catenin signaling pathway that determines normal tissue homeostasis, aberrant activation of β-catenin–T-cell factor (TCF) is a hallmark of colorectal cancer ^[72]. β-catenin is known to mediate tumor metastasis through interactions with Ezrin and the NF-κB pathway ^[73].

3.11. EGFR

EGFR (epidermal growth factor receptor) regulates epithelial cell growth and is overexpressed in various metastatic tumors ^[74]. Upon cell contact, ectopic apical Ezrin can increase cortical cytoskeleton contractility and EGFR internalization ^[75]. In non-small cell lung cancer (NSCLC) cells, Ezrin was found to enhance EGFR signaling and regulate EGFR trafficking to the nucleus. When Ezrin expression is inhibited, both EGF-induced phosphorylation and nuclear translocation of EGFR are reduced.

3.12. FAS

Fas, also known as CD95, apoptosis antigen 1 (APO-1), or tumor necrosis factor receptor superfamily member 6 (TNFRSF6), is a death receptor encoded by the FAS gene. Fas can trigger apoptosis in various cell types, where Fas activation can lead to the formation of a death-inducing signaling complex ^[76]. Human T lymphocytes undergo cell membrane polarization through an Ezrin-mediated interaction with the actin cytoskeleton, where Ezrin and Fas both colocalize at the polarization site.

3.13. ICAM1, ICAM2, and ICAM3

ICAM-1, ICAM-2, and ICAM-3, intercellular adhesion molecules 1, -2, and -3, are cell surface glycoproteins encoded by the ICAM1, ICAM2, and ICAM3 genes, respectively. ICAMs mediate binding to leukocyte β₂ integrins (CD11/CD18) such as LFA1 and Mac1 during inflammation and immune response ^[77]. Ezrin is directly involved in ICAM-2 subcellular distribution and adhesive function, where Ezrin can trigger the redistribution and accumulation of ICAM-2 in uropods ^[78]. PIP₂ can enhance Ezrin and ICAM-2 interaction. ICAM-3, in contrast, did not bind with Ezrin despite the presence of PIP₂ ^[45].

3.14. IQGAP1

IQ motif containing GTPase activating protein 1 (IQGAP1) is a scaffolding protein encoded by the IQGAP1 gene and functions in metastatic signaling pathways by recruiting signaling intermediates for efficient signal transduction ^[79]^[80]. Ezrin interacts with IQGAP1 at the FERM domain, forming a hub for concentrating signaling complexes. Both Ezrin and IQGAP1 colocalize in the submembranous cytoskeleton and cellular protrusions of human epithelial cells, and when Ezrin is knocked down, the cortical localization of IQGAP1 is reduced ^[81].

3.15. L1CAM

L1CAM (L1 cell adhesion molecule) is a glycoprotein encoded by the L1CAM gene and is involved in cell adhesion and migration. L1CAM expression is frequently upregulated in cancer patients and has a distinct role in the metastatic cascade, promoting dissemination, colonization, and metastatic growth ^[82]. In ESCC, L1CAM was found to upregulate the expression of Ezrin through activation of integrin β1/MAPK/ERK/AP1 signaling and promoted tumorigenicity ^[83].

3.16. MSN

The MSN gene encodes Moesin (Membrane-Organizing Extension Spike Protein), part of the ERM family of proteins that link the plasma membrane with actin filaments. Moesin is highly expressed in the lungs, spleen, kidneys, and endothelial cells ^[36]. Its phosphorylation at Thr558 activates Moesin to its open conformation. While sharing many properties similar to Ezrin and Radixin, the three family members have distinct and overlapping distribution patterns that coincide with their functions and roles.

3.17. NF2

The neurofibromatosis type 2 gene (NF2) encodes a tumor suppressor of Moesin–Ezrin–Radixin-Like Protein (Merlin). A member of the FERM domain-containing 4.1 superfamilies, Merlin shares an evolutionarily conserved domain and sequence homology with ERM proteins but lacks the actin-binding site on the C-ERMAD domain, instead having a unique actin-binding motif in the FERM domain ^[84]. Merlin plays a key role in contact inhibition of cell proliferation and signal transduction, regulating pathways such as PI3K/AKT, Raf/MEK/ERK, and mTOR ^[85].

3.18. PALLD

PALLD encodes palladin, a component of actin-containing microfilaments that control cell shape and adhesion. Part of the myotilin/myopalladin/palladin family, palladin is primarily expressed in smooth muscle and nonmuscle, localizing along actin microfilaments in a periodic manner typical for components of dense bodies of smooth muscle in stress fibers ^[86].

3.19. PRCKA

Protein kinase C alpha (PKCα) is an enzyme encoded by the PRCKA gene. PKCα has been implicated in promoting β1 integrin-mediated cell migration as part of the protein kinase C family. PKCα overexpression is associated with increased cell motility and invasive potential ^[48]. As stated, PKCα forms a molecular complex with Ezrin, which is hyperphosphorylated at Thr567, activating Ezrin and driving the migratory response ^[21].

3.20. PTK2

Protein tyrosine kinase 2 (PTK2), also known as focal adhesion kinase (FAK), is an enzyme encoded by the PTK2 gene. FAK is important in various cell functions, including motility, adhesion, metastasis, invasion, survival, apoptosis, and angiogenesis ^[87]. It has also been found to play an important role in EMT, cancer stem cells, and tumor microenvironments ^[88].

3.21. RDX

The RDX gene encodes Radixin, part of the ERM family of proteins that link the plasma membrane with actin filaments. Radixin is highly expressed in the liver, and phosphorylation at Thr564 activates Radixin to its open conformation. Like Ezrin and Moesin, Radixin is overexpressed in many tumor tissues ^[89] and can modulate the viral infection process for several viruses by regulating stable microtubule function ^[90]. The knockdown of Radixin by shRNA in glioblastoma U251 cells was found to significantly inhibit tumor growth and upregulate thrombospondin-1 (TSP-1) and E-cadherin while downregulating MMP9 ^[91].

3.22. RHOA

RhoA (Ras homolog family member A), a protein encoded by the RHOA gene, is part of the Ras superfamily of small guanosine triphosphatases (GTPases). RhoA plays a critical role in signal transduction, regulating cell morphology, growth, movement, and the cell cycle by switching between its inactive GDP-bound form to its active GTP-bound form ^[60]. Ezrin interacts with RhoGDI by dissociating it from RhoA, thus allowing RhoA to activate. Podocalyxin, a major protein in podocytes, has been shown to associate with Ezrin in recruiting RhoGDI to activate RhoA and actin reorganization ^[92]. RhoA has also been shown to regulate breast cancer metastasis as an upstream signaling factor of Ezrin, where increasing RhoA phosphorylation resulted in enhanced Ezrin expression ^[93]^[94].

3.23. ROCK1

Rho-associated, coiled-coil-containing protein kinase 1 (ROCK1) is a serine/threonine protein kinase that plays a significant role in the actomyosin cytoskeleton and is encoded by ROCK1. ROCK1 is a major downstream effector of RhoA and plays a large role in cell motility, metastasis, and angiogenesis ^[95]. ROCK1 has been shown to phosphorylate Ezrin at Thr567 ^[96].

3.24. S100P

S100 calcium-binding protein P (S100P) is an EF-hand protein encoded by the S100P gene. S100 proteins are involved in the regulation of membrane–cytoskeleton interactions and cytoskeleton dynamics. Dimeric S100P was found to bind to and activate dormant Ezrin in a Ca²⁺-dependent manner. S100P can also unmask the F-actin binding site on Ezrin, partially activating Ezrin in response to Ca²⁺ stimulation ^[97].

3.25. SCYL3

SCYL3 encodes the protein PACE-1 (protein-associating with the carboxyl-terminal domain of Ezrin). Initially characterized in human breast cancer cells, PACE-1 binds to the C-terminal domain of Ezrin and colocalizes with Ezrin in the lamellipodia. It may regulate cell adhesion/migration complexes and could function as a scaffold protein to bring kinase activity near Ezrin ^[98].

3.26. SDC2

Syndecan-2, a cell surface heparan sulfate proteoglycan encoded by the SDC2 gene, mediates cell–cell and cell–matrix adhesion and cytoskeletal organization. The N-terminal domain of Ezrin binds to syndecan-2 in a dose-dependent manner, where syndecan-2 contains a specific and unique Ezrin-binding sequence, suggesting a distinct regulation ^[99]. In fibrosarcoma, IGF-I is an anabolic growth factor that can promote tumorigenesis by inhibiting apoptosis and promoting cell cycle progression. IGF-I enhanced Ezrin phosphorylation levels, SDC-2 expression, and the formation of an SDC-2 and Ezrin complex. It was also revealed that SDC-2 colocalizes to the IGF-I receptor for recruiting Ezrin in the plasma membrane to enhance actin polymerization, ultimately facilitating IGF-I-dependent fibrosarcoma cell migration ^[100].

3.27. SELL and SELP

Selectin L (CD62L) and Selectin P (CD62P), encoded by the SELL and SELP genes, are transmembrane proteins functioning as cell adhesion molecules. Selectin L contains an ERM binding domain; mutants with defective ERM binding have decreased microvilli localization and reduced tethering to Selectin P glycoprotein ligand-1 (PSGL-1), suggesting an important role for ERM proteins in Selectin L function ^[101].

3.28. SLC9A1

SLC9A1 (solute carrier family 9, member A1) encodes Na⁺/H⁺ exchanger 1 (NHE1), a membrane protein that transports Na+ into the cell and H⁺ out of the cell. Localized in invadopodia, the upregulation of NHE1 has been correlated with tumor malignancy ^[102]^[103]^[104]^[105]. NHE1 acts as a scaffold protein and interacts with numerous proteins through its regulatory C-terminus ^[106]. At the C-terminal tail, NHE1 contains two ERM protein-binding motifs, and this interaction regulates many important cellular events such as cell migration, signaling complexes, and resistance to apoptosis ^[107]^[108]^[109].

3.29. SLC9A3R1

Na⁺/H⁺ exchanger 3 regulatory factor 1 (NHERF1) or ERM-binding phosphoprotein 50 (EBP50) is encoded by the SLC9A3R1 (solute carrier family 9, member 3 regulator 1) gene. NHERF1/EBP50 is a PDZ-scaffold protein that significantly regulates the cancer signaling network by assembling cancer-related proteins ^[110]. Scaffold proteins coordinate specific signaling pathways by locally concentrating, compartmentalizing, and positioning transporters/receptors or enzymes in the vicinity of their substrates ^[111]^[112]^[113]^[114].

3.30. SLC9A3R2

SLC9A3R2 (solute carrier family 9, member 3 regulator 2) encodes a PDZ-scaffold protein of Na⁺/H⁺ exchanger 3 regulatory factor 2 (NHERF2). NHERF2 shares about 52% amino acid identity with EBP50 and has the same PDZ domain structure ^[115]. Both EBP50 and NHERF2 play an essential role in the NHE3/Ezrin/cAMP-dependent protein kinase II signaling complex, a process required for ion transport inhibition through the phosphorylation of NHE3 ^[116]^[117]. EBP50, NHERF2, and ERM have a distinct cell-type-specific expression that parallels their binding preferences ^[118].

3.31. SNX27

Sorting nexin 27 (SNX27) is a sorting nexin family member and plays a critical role in the endosomal recycling of many transmembrane receptors. SNX27 contains a Phox homology domain that binds to phosphatidylinositol phospholipids and regulates its localization to the endosome, as well as a PDZ (Psd-95/Dlg/ZO1) domain and an atypical FERM domain that both function to bind to cargo receptors containing a short NPxY sequence motif ^[119]^[120]. SNX27 interacted with the small GTPase Ras, which has been implicated in oncogenic signaling pathways ^[121]. The Ras interaction arises through the FERM F1 subdomain, suggesting that other FERM domain proteins share a similar binding activity ^[122].

3.32. SPN

SPN encodes CD43 (also known as sialophorin or leukosialin), a sialoglycoprotein that plays an essential role in T lymphocyte activation, proliferation, apoptosis, and migration. It was found that both Ezrin and Moesin interact with CD43, regulating its redistribution to T lymphocyte uropods and inhibiting T cell and APC interaction ^[123]. This interaction can facilitate transendothelial migration and T lymphocyte recruitment ^[124].

3.33. TSC1

TSC1 (tuberous sclerosis-1) is a tumor suppressor protein encoded by the TSC1 gene. TSC1 was found to regulate cell adhesion through its interaction with ERM proteins and Rho ^[125]. Interaction with Ezrin is required to activate Rho and inhibit TSC1 function in cells containing focal adhesions, resulting in loss of adhesion to the cell substrate.

3.34. VCAM1

Vascular cell adhesion molecule-1 (VCAM-1) is a cell adhesion molecule encoded by the VCAM1 gene. VCAM-1 interacts with Ezrin and Moesin during leukocyte adhesion and transendothelial migration, and all three colocalize at the apical surface of the endothelium. An endothelial docking structure forms from the clustering of VCAM-1, ICAM-1, and activated Ezrin and Moesin during leukocyte adhesion, anchoring and partially embracing the leukocyte ^[126].

4. Role of Ezrin in Immunity to Prevent Immune Attack

Ezrin is primarily known for connecting membrane proteins to the actin cytoskeleton ^[14]^[127]. This process has been linked to the metastatic behavior of tumors, where adhesion molecules, through Ezrin-mediated linkages to actin, confer to tumor cells the capacity to migrate within tissues, through vessels, and attach to metastatic organs ^[128]^[129]. However, Ezrin has also been implicated in many interactions with the immune system that protect cells from immune attack (Figure 2).

/media/item_content/202306/649798b21feffcells-12-01620-g004.png

Figure 2. Ezrin is critical for metastasis and regulates multiple steps of the metastatic process in a variety of ways. (A) Ezrin expression in tumor cells promotes many interactions between tumor cells and the immune system, protecting metastatic tumor cells from immune cell attack. (B) Upregulated Ezrin in metastatic tumor cells helps regulate all steps of the metastatic cascade, including initial dissemination, circulation, seeding, colonization, and survival at distant organ sites. For example, Ezrin controls the EMT molecules to initiate tumor migration and invasion from the primary site in the intravasation step. Disseminating tumor cells enter the bloodstream and highly express Ezrin for tumor cells’ movement in circulation. The circulating tumor cells with higher Ezrin expression are more closely associated with distant metastasis. Ezrin and PODXL directly interact to rearrange the cytoskeleton to change cell morphology towards an invasive extravasation-competent shape. Lastly, Ezrin also promotes the survival of tumor cells at distant organs following extravasation.

Tumor cells have been found to exhibit phagocyte-like behavior; studies have shown dead cells and undefined particles phagocytosed within various tumor cells ^[130]^[131]. Cell lines derived from metastatic tumors also exhibited vigorous phagocytic activity ^[129].

Ezrin also interacts with other immune cells to promote metastasis and has been found to influence immune cell polarization, emigration, and intracellular adhesion. In pancreatic ductal adenocarcinoma (PDAC), PDAC-derived small extracellular vesical Ezrin (sEV-EZR) was found to regulate macrophage polarization and promote PDAC metastasis ^[132].

5. Ezrin as a Target for Treating Metastatic Disease

Ezrin has been widely studied as a possible therapeutic target for treating metastatic disease. This is due to its identification as a critical regulator of metastasis in several cancers ^[133], playing a role in nearly every step of the metastatic cascade (Figure 2).

To successfully metastasize, the tumor cell must make numerous adjustments and survive a series of challenges involving intravasation, blood or lymph system circulation, extravasation, and growth at distant organs ^[134]. In line with this, Ezrin has been implicated in many steps of the metastatic cascade, and many of these steps have been mentioned previously. Ezrin plays a large role in EMT, which initiates the escape of cancer cells from their primary site and enhances their migratory capacity and invasiveness ^[135]. Here, Ezrin can control the function of various EMT-associated transcription factors, such as Snail and Twist ^[136], and activate signaling pathways that facilitate the EMT process, such as the NF-κB pathway ^[137].

6. Conclusions

Since its discovery in 1983, the knowledge and understanding of Ezrin’s biology and function have continuously expanded. Its role as a linker between the plasma membrane and cytoskeleton has been well studied, as many of its functions described here have contributed to its role in tumor metastasis. Modulating several of the membrane–cytoskeleton interactions, maintaining the cell shape and structure, and regulating cell–cell adhesion, as well as regulating cell movement, can confer to tumor cells the ability to survive and successfully metastasize. Additionally, its regulation by many signaling molecules through phosphorylation and conformational changes heavily dictates its function. Ezrin also has a host of binding partners that can explain how Ezrin is intertwined in various oncogenic signaling pathways.

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Subjects: Cell Biology

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Rand Gabriel M. Buenaventura

Glenn Merlino

Yanlin Yu

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Update Date: 25 Jun 2023

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