Caveolin proteins: a molecular insight into disease

Abstract

Caveolae are a kind of specific cystic structures of lipid rafts in the cytoplasmic membrane and are rich in cholesterol and sphingolipids. In recent years, many researchers have found that both caveolins and caveolae play a role in the development of various human diseases, including coronary heart disease, hypertension, and nervous system disorders. The specific mechanisms by which caveolins induce diseases have been a topic of interest. However, a number of detailed molecular mechanisms remain poorly understood. This article focuses on the relationship between caveolin proteins and human diseases and reviews the molecular mechanisms of caveolins in disease networks.

Keywords

caveolin / caveolae / microRNA / disease / signaling pathway / heart / tumor

Short presentation of caveolin and caveolae

The earliest research on caveolae was initiated by Yamada and Palade in 1955. The word “caveolae,” meaning “small sag” or “little cave,” is used to describe the membrane flask-shaped invaginations observed in epithelial cells [ 1]. In 1992, a 22–24 kDa protein called V1P21 was cloned and identified [ 2]. In subsequent studies, researchers realized that this molecule was not only the important protein to mediate the formation of caveolae but also the key protein in the caveolae structure. V1P21 can form the caveolae structure with special lipids; therefore, V1P21 was named caveolin [ 3]. Caveolin proteins are the surface marker proteins of the caveolae. The caveolin family consists of three members: caveolin-1, caveolin-2, and caveolin-3 [ 4]. The caveolin family molecular gene locations and the properties of their protein products are listed in Table 1. These protein products are expressed mostly in mammals, but their expression levels vary in different tissue [ 5]. Caveolin-1 and caveolin-2 are widely expressed on the surface of a variety of tissue cells, and they are commonly expressed in the same cell. These two molecules are rich in type-I alveolar cells, vascular endothelial cells, fibroblasts, and adipose cells. At present, researchers believe that caveolin-1 interacts with caveolin-2 to form a kind of macromolecule heterooligomer. Unlike caveolin-1 and caveolin-2, caveolin-3 is mainly expressed in differentiated skeletal muscle cells and myocardial cells [ 6]. Different distributions demonstrate that caveolin-3 demonstrates different physiological functions. Studies found that caveolin-1 is related to the occurrence, development, and metastasis of tumors, as well as cell proliferation and molecular signal transduction. The deletion of caveolin-2 function is similar to that of caveolin-1, whereas caveolin-3 is thought to be associated with muscular dystrophy. Furthermore, the genes of caveolin-1 and caveolin-2 are located in chromosomal 7 (7q31.1–31.2 in humans), and these two genes are closely linked, whereas caveolin-3 gene is located on human chromosome 3p25 [ 7]. Nevertheless, these three molecules generally exhibit the same monolithic construction and similar hydrophobic transmembrane segments, namely, hydrophilic N-terminal and C-terminal.

In recent years, researchers have discovered that the structures of caveolae and caveolin proteins play an important role in cellular physiological functions, particularly those related to cholesterol transport, cell signal transduction, endocytosis, and tumor suppression [ 8]. Caveolae and caveolin are abnormally expressed in various diseases, such as cancer, atherosclerosis, muscular dystrophy, and Alzheimer’s disease [ 9]. This review article mainly presents the molecular properties and functions of the caveolin family members (Fig. 1).

Caveolin-1 and diseases

Biological characteristics of caveolin-1 protein

Caveolin-1 is the main protein ingredient of caveolae, and the caveolin-1-coding gene is located in human chromosome 7q31.1, which is between the D7S522 and D7S2460 sites. Caveolin-1, with a transcript length of 2704 bp, contains three exons, encodes 178 amino acid residues of protein, and presents an open reading frame consisting of 537 bp [ 10]. Caveolin-1 significantly influences the inner surface of the caveolae, and this surface maintains the caveolae’s structure, shape, and function. Hence, the caveolae are needed to form the flask structure [ 11].

Currently, caveolin-1 has been divided into two subtypes: α and β. Caveolin-1 widely exists in endothelial cells, smooth muscle cells, skeletal muscle cells, fibroblasts, type-I alveolar cells, and fat cells [ 12]. Caveolin-1 is also expressed in the brain and spinal cord neurons and glial cells [ 13]. The change of caveolin-1 gene expression can lead to many diseases. By reviewing previous research results, we can summarize the relationship between caveolin-1 and diseases. In the following section, we report that caveolin-1 is involved in central nervous system diseases, occurrence of tumors, and pulmonary fibrosis.

Caveolin-1 and central nervous system diseases

Caveolin-1 exerts varying effects on the central nervous system [ 14]. Caveolin-1 impedes cell proliferation and migration of vascular smooth muscle cells (VSMCs) [ 15], thus inhibiting cerebral atherosclerosis and reducing the occurrence of ischemic cerebrovascular disease. However, in some research, caveolin-1 exacerbated ischemic cerebrovascular disease [ 16]. Chen et al. [ 17] found that caveolin-1 may assist calcitonin gene-related peptides in suppressing VSMC proliferation. In particular, caveolin-1 reduces the neurotransmission of p-ERK1/2 through coupling between caveolin-1 and p-ERK1/2. However, some studies have indicated that caveolin-1-deficient cells lose the capability of directional migration, and normal polarization disappears because RhoA expression decreased, whereas Rac and Cdc42 expression increased, thereby inhibiting the formation of the necessary structure of cell migration. Chen et al. suggested that caveolin-1 promotes the migration of smooth muscle cells [ 18]. Furthermore, Jasmin et al. [ 19] used caveolin-1 gene knockout mice to study the function of caveolin-1 in cerebral ischemic injury; their study showed that cerebral ischemia induced a marked increase in caveolin-1 and caveolin-2 proteins in the endothelium, and caveolin-1 gene knockout mice resulted in an increase of cerebral infarction volume. From the mechanism, the ischemic brains of caveolin-1 gene knockout mice showed impaired angiogenesis and increased apoptotic cell death. On the contrary, by comparing the wild-type mice and caveolin-1 knockout mice, Li et al. found that brain neural stem cells differentiating into glial cells significantly decreased in caveolin-1 knockout mice. Notch intracellular domain and hairy enhancer of split 1, which are located in the Notch signaling pathway, also significantly decreased. By adding caveolin-1 to the neural stem cell medium, Li et al. found that neural stem cells differentiating into glial cells increased, and NICD and Hes1 in the Notch signaling pathway were upregulated. Li et al. suggested that caveolin-1 expression decreased in ischemic cerebrovascular disease, which consequently reduced the differentiation of neural stem cells into astrocytes and is beneficial to nerve regeneration and functional recovery of patients with ischemic cerebrovascular disease [ 20]. In conclusion, caveolin-1 protein might be upregulated or downregulated in ischemic cerebrovascular disease. However, whether caveolin-1 protein is beneficial or harmful still requires further research.

Additionally, some research showed that cholesterol played a major role in the pathology of Alzheimer’s disease (AD) [ 21]. The main pathological characteristic and pathogenesis of AD implies that amyloid precursor protein (APP) is hydrolyzed by β-secretase and g-secretase, thus causing the deposition of the brain amyloid β-peptide (Aβ) [ 22]. Caveolin-1 is closely related to the pathological substances of AD and APP or Aβ [ 23]. High cholesterol in AD patients causes the upregulated expression of caveolin-1 [ 24], and caveolin-1 overexpression promotes APP splitting to Aβ [ 25]. Caveolin-1 expression also promotes oxidative stress, inducing premature senility [ 26]. However, in some research, caveolin-1 expression inhibited the generation of Aβ to prevent the occurrence of AD [ 27]. Apparently, the effect of caveolin-1 on AD still needs further research.

Caveolin-1 and the occurrence of tumors

At present, the relationship of the caveolin-1 gene with tumor development is receiving considerable attention. The caveolin-1 protein plays a major role in the regulation of cell differentiation, proliferation, migration, apoptosis, and other functions [ 28]. A recent study also reported that caveolin-1 exerts a dual effect on tumor development.

Numerous studies have indicated that caveolin-1 is highly expressed in normal tissue, and caveolin-1 expression significantly decreases in breast, lung, cervical, ovarian, and colon cancers. The following paragraph clearly illustrates the specific mechanisms of caveolin-1 inhibiting tumor occurrence. Hulit et al. [ 29] showed that the normal expression of caveolin-1 can inhibit the activity of the promoter of cyclin-D1 gene, and the place of action is the N-terminal of caveolin-1; thus, caveolin-1 can inhibit cell growth. Caveolin-1 also inhibits the mitogen-activated kinase (MAPK) pathway. The main members of the MAPK family are JNK and ERK, and caveolin-1 can inhibit ERK activation through many ways, such as by blocking the downstream transmission of signals [ 30]. Li et al. [ 31] found that caveolin-1 inhibits the phosphorylation of SRC tyrosine kinase, thereby preventing the downstream transmission of signals and inhibiting the malignant transformation of cells.

However, recent studies have found that caveolin-1 is highly expressed in some tumor tissue, such as in renal cell carcinoma, bladder cancer, and prostate cancer. This phenomenon demonstrated that the increase of caveolin-1 is related to the occurrence and development of tumors. The abovementioned study showed that caveolin-1 promoted malignant transformation of cells through the following ways. (1) Point mutation. In breast cancer research, Leeet al. [ 32] found that the mutation rate of caveolin-1 gene 132nd (P132L) can reach up to 16%. P132L expression in HIH3T3 cells can enhance the capability of invasion and drug resistance of cells. (2) Serine phosphorylation of caveolin-1. Generally, caveolin-1 is associated with the cytoplasmic membrane, but when its Ser80 site is phosphorylated, caveolin-1 can become a secreted protein. The secreted caveolin-1 can increase the survival ability of tumors with autocrine or paracrine function. (3) Tyrosine phosphorylation of caveolin-1. Tyrosine phosphorylation at different sites in the caveolin-1 protein may cause resistance to the tumor suppression capability of the caveolin-1 scaffolding domain [ 33]. Thus, the function of caveolin-1 in cancer is complex, but the specific mechanisms remain unclear and need further study.

Caveolin-1 and pulmonary fibrosis

Caveolin-1 is largely expressed in normal lung tissue of alveolar type-I epithelial cells, endothelial cells, and fibroblasts, whereas caveoilin-1 expression is minimal in alveolar type-II epithelial cells. Caveolin-1 plays an essential function in pulmonary diseases, such as pulmonary hypertension, fibrosis, immune defects, and increased endothelial permeability. Current research regarding caveolin-1-dependent regulation of pulmonary cell functions will be presented here along with the research findings in pulmonary fibrosis regulated by caveolin-1.

Kasper et al. [ 34] found that after cadmium chloride and transfer growth factor (TGF)-β1 treatment in the lung tissue of rats, caveolin-1 expression in endothelial cells was significantly downregulated. In 2004, Koslowski et al. [ 35] reported that the use of bleomycin to handle the alveolar epithelial cell line R3/1 significantly decreased caveolin-1 expression. Caveolin was shown to be a potential early indicator of epithelial cell dysfunction in pulmonary fibrosis. Drab et al. [ 36] discovered that the lungs of caveolin gene knockout mice presented lesions similar to those found in pulmonary fibrosis. Pulmonary fibrosis lesions can be improved by reconstructing caveolin-1 expression in caveolin-1 gene knockout mice [ 37]. The above studies illustrated that caveolin-1 might be an inhibitory factor in pulmonary fibrosis. Caveolin-1 and TGF-β1 type-I receptor, TGF-β type-II receptor, and Smad-2 were colocated in the abundant regions of the cell plasma membrane. Caveolin scaffolding domain (CSD) is the region of caveolin-1 which interacts with other signaling molecules. Caveolin-1 interacts with TGF-β1 type-I receptor [ 38] and type-II receptor [ 39] through CSD, by regulating the binding of TGF-β1 and receptor negatively and inhibiting Smad-2 phosphorylation, thereby blocking Smad-2 connection with Smad-4. Finally, caveolin-1 blocks the nuclear translocation of Smad-2/3/4 compounds and the signaling pathway of TGF-β1/Smad. Moreover, TGF-β may trigger Smad-independent pathways, such as mitogen-activated kinases. In this signaling pathway, the p42/44 MAPK, which is a known activator of collagen synthesis, is upregulated in lung fibroblasts of scleroderma patients or in caveolin-1 knockdown mice [ 40]. These findings highlight the specific mechanism indicating that the decrease of caveolin-1 contributes to pulmonary fibrosis.

Other functions of caveolin-1

In addition to the above functions, caveolin-1 mediates other diseases. Studies have shown that the abnormal expression of caveolin-1 is involved in respiratory diseases [ 41], and re-expression of caveolin-1 can play a protective role in the heart [ 42, 43]. Recent evidence has shown that the increased expression of caveolin-1 facilitates repair in intervertebral disc degeneration by enhancing TGF-β signaling [ 44]. Caveolin-1 also regulates corneal wound healing by modulating Kir4.1 activity [ 45].

Caveolin-2 and diseases

Biological characteristics of caveolin-2 protein

In 1996, Schere et al. [ 46] used microsequencing to identify caveolin-2. The distribution of caveolin-2 is similar to that of caveolin-1, which is mainly expressed in skeletal myoblasts, endothelial cells, and fibroblasts. Many studies have shown that caveolin-2 forms the heterologous oligomer complexes with caveolin-1 [ 47], and caveolin-1 and caveolin-2 were colocalized and co-expressed within the plasma membrane [ 48]. Intracellular transport of caveolin-2 needs participation of caveolin-1; thus, caveolin-2 is possibly the accessory protein of caveolin-1 [ 49]. Although caveolin-2 was colocated with caveolin-1 in different cells, the expression of caveolin-1, -2, and-3 can be independently downregulated or upregulated. In addition, some research pointed out that the change of caveolin-2 expression induces diseases independently. To date, few reports exist about caveolin-2 in diseases. Hence, in this paper, we will provide a brief overview of caveolin-2-related diseases.

Caveolin-2 and pulmonary diseases

In 2002, by examining the phenotype and histology of Cav2^−/− mice, Razani et al. [ 50] found that Cav2^−/− mice presented severe pulmonary dysfunction, and this finding confirmed the uniqueness of caveolin-2 function. In caveolin-2-deficient mice model, caveolae was still formed and distributed in the membrane. Furthermore, in specific tissue, knocking out caveolin-1 and caveolin-2 resulted in a large amount of cell proliferation in the lung parenchyma and incrassation of airway epithelial cells; this result indicated that the decrease of caveolin expression may promote the occurrence of lung cancer. Nonetheless, the specific mechanisms of caveolin-2 involved in pulmonary dysfunction and lung cancer remain to be further studied.

Caveolin-2 and central nervous system diseases

Caveolin-2 presents a certain amount of expression in normal brain tissue, and recent studies have found that caveolin-2 is related to the physiological or pathological changes of brain function [ 51]. Zhao et al. [69] have confirmed that caveolin-2 expression is increased markedly in tissue of focal cerebral ischemia/reperfusion (I/R), with simultaneous change of blood–brain barrier (BBB) permeability. The results showed that caveolin-2 played a role in the increase of BBB permeability induced by I/R damage.

Jasminet al. [ 19] used caveolin gene knockout mouse model to evaluate the functional role of caveolin in cerebral ischemic injury. These studies have shown that cerebral ischemia induces a marked increase in caveolin-1 and caveolin-2 proteins in the endothelium.

Caveolin-2 and human cancer

Leeet al. [ 52] detected the caveolin-2 expression level in various cancer cells and tested the proliferation of cancer cells after knocking out caveolin-2 or overexpressing caveolin-2. Shatsevaet al. [ 53] found that miR-199a-3p promotes proliferation and survival of endothelial cells, as well as breast cancer cells by targeting caveolin-2. Yamasakiet al. [ 54] showed that miR-218, a kind of tumor suppressor, can mediate cell proliferation, migration, and invasion in A498 and 786-O renal cell carcinoma cell lines by targeting caveolin-2. In other cancer cells, such as breast cancer, ovarian adenocarcinomas, and colon carcinomas, the caveolin-2 expression was suppressed [ 55, 56]. Nevertheless, the specific mechanisms by which caveolin-2 regulated cancer need further research.

Other functions of caveolin-2

López et al. [ 57] showed that caveolin-2 performs a function in lipid metabolism and storage, indicating that caveolin-2 as candidate gene is involved in diet-induced obesity. The reduced expression of caveolin-2 also significantly weakens the capacity of Pseudomonas aeruginosa to invade MLE-12 cells. Moreover, the lipid raft-dependent tyrosine phosphorylation of caveolin-2 might be an important regulator of P. aeruginosa invasion [ 58]. In 2016, Tottaet al. found that caveolin-2 was a critical regulator of 17β-estradiol-dependent cell proliferation [ 59].

Caveolin-3 and diseases

Biological characteristics of caveolin-3 protein

In 1996, Tanget al. [ 60] first identified the third member of the caveolin protein family and found that a high level of caveolin-3 only existed in T-tube and microcapsule in skeletal and cardiac muscles, which indicated that the caveolin-3 protein played a special role in muscle cells.

The human caveolin-3 gene is located in 3p25 containing two exons, corresponding to the 6E1 region in mice [ 61]. Caveolin-3 is a protein composed of 151 amino acids, and its transmembrane domain consists of 33 amino acids located in the center [ 62]. N- and C-terminals are free in the cytoplasm. The N-terminal 41 amino acids (61–101) consist of CSD, and the C-terminal area is composed of three palmitin parts [ 63]. Generally, the three caveolin molecules exhibit the same structure and hydrophilic N- and C-terminal, but caveolin-1 and caveolin-3 presented higher homology, that is, their amino acid sequences are the same at 85%.

Caveolin-3, the muscle cell-specific protein, is involved in the formation of caveolae in muscle cells and other diseases. In the following section, we will discuss the findings indicating that caveolin-3 is involved in cardiac hypertrophy and muscular dystrophy.

Caveolin-3 and cardiac hypertrophy

Cardiac hypertrophy is mainly manifested through the hypertrophy of cardiomyocytes and the changes of interstitial components (or cardiac remodeling). Cardiac compliance and the function of circulating pump decreased. Initial cardiac hypertrophy demonstrates a certain compensatory significance, but persistent cardiac hypertrophy eventually leads to dilated cardiomyopathy, heart failure, and even sudden death [ 64].

The endocrine system of the heart and the cell signal transduction pathways mediated by its receptor, mechanical tension receptor, and its signal transduction pathways play an important function in cardiac hypertrophy. Yamazaket al. have shown that the signal transduction pathways of G protein, protein kinase C (PKC), and MAPK are important signals in the process of cardiac hypertrophy. To date, research has focused on the role of caveolin-3 in myocardial cell signal transduction. Caveolin-3 is the main component of caveolae in cardiac cells. By using nuclear magnetic resonance imaging and chest wall echocardiography, Woodmanet al. found that Cav3^−/− mice presented significant cardiac hypertrophy. Recently, some researchers have found that caveolin-3 overexpression relieves cardiac hypertrophy and plays a protective role in the heart through two possible mechanisms. First, in cardiomyocytes, the increased expression of caveolin-3 forms complexes with PKCα, inhibiting the coupling of PKCα with Cav3.2 channels during the process, which can inhibit nuclear translocation of NFAT and attenuate hypertrophic responses. The other mechanism implies that caveolin-3 overexpression directly suppresses T-type calcium current (ICa,T) [ 65].

Caveolin-3 and muscular dystrophy

Caveolin-3 is specifically expressed in the caveolae and T tubes of skeletal muscle and myocardium [ 60]. Several studies have shown that various muscle cell surface molecules are associated with caveolin-3. Stoppani et al. have found that caveolin-3 knockout mice will cause more severe phenotypes and is characterized by the simultaneous attenuation of Akt protein and p38 signaling network, thereby leading to the appearance of immature cells [ 66]. In addition, the decrease of caveolin-3 is related to the Smad2 and Erk1/2 pathways induced by TGF-β, which confirms that caveolin-3 controls the signaling pathway of TGF-β in the plasma membrane. TGF-β type-1 receptor (TβRI) kinase inhibitors also enable caveolin-3 to become a drug against muscle atrophy in a variety of clinical treatments.

Other functions of caveolin-3

Leiet al. [ 67] reported that overexpression of caveolin-3 attenuates diabetic cardiomyopathy induced by activation of PKCβ₂ via the Akt/eNOS/NO signaling pathway. Recently, Tranet al. [ 68] have investigated the role of caveolin-3 in modulating lymphocytes and demonstrated that caveolin-3 is involved in lymphocyte proliferation, differentiation, and apoptosis.

Prospective

The caveolin gene family has become a strong topic in research. Studies on the biological function of caveolae have shown that both caveolae and caveolin are involved in the occurrence and development of many diseases. At present, caveolin plays a pivotal role in signal transduction and also exerts a direct regulatory effect in a variety of key signaling molecules, particularly in negative regulation. Thus, caveolin is involved in the pathological and physiological processes of cell differentiation, proliferation, tumor occurrence, cardiac hypertrophy, and senescence. Clarification of the role of caveolin gene family members in human diseases and the relationship between these two is valuable to understand the occurring mechanism of human diseases and medication development. Further research on the mechanism of abnormal caveolin expression and its involvement in diseases can provide new insights into the treatment of many diseases.

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