RASA1 and Associated Diseases

Rasp21 protein activator 1 (RASA1) is an important activity regulator in cells, which participated in many important physiological processes.

Structure of RASA1

RASA1 contains four key domains, N-terminal domain, pleckstrin homology domain, Src homology domain and GTPase activator domain. The Src homology domain (SH2/SH3) is responsible for the interaction with other proteins, and the PH domain is responsible for connecting with the Btk motif. When the intracellular Ca²⁺ level increases, the C2 domain located at the N-terminus allows RASA1 to bind phospholipids, while the PH structure remains inactive to prevent lipid binding. In fact, RASA1 is a dual-specific GAP that can simultaneously manipulate the enzymatic activities of Ras and Rap in cells.

Fig 1. Domains of RASA1. (Zhang, 2020)

Function of RASA1

Under normal circumstances, RASA1 is soluble in the cytoplasm and can be recruited to the plasma membrane in a Ca²⁺ level-dependent manner. RASA1 participates in a series of cellular physiological functions. The best-studied physiological role of RASA1 is to regulate blood vessel development. RASA1 prevents the phosphorylation of Ras, thereby affecting the PI2K/Akt signaling pathway, and inhibiting the growth and migration of vascular smooth muscle cells. This pathway has also been found to be critical for endothelial tube network assembly during angiogenesis during development. In addition, RASA1 also interacts with Ephrin-type B receptor 4 and mitogen-activated protein kinase 4, which are capable of repairing ischemic injury and are in charge of the development of lymphatic vessels, respectively.

RASA1 also plays an important role in the immune system. Research have shown that the motility of macrophages, adhesion structure and cytoskeleton are directly regulated by GRLF1 translocation which is mediated by RASA1, and the normal expression of RASA1 is essential for the genesis of T cells.

Fig 2. The role of RASA1 in lymphocyte development. (Chen, 2020)

In fact, with the advancement of molecular biology, the function of RASA1 in neuron development, follicle/epididymis development and wound healing has also been studied in depth. Some physiological functions related to RASA1 and possible influencing molecules are listed below.

Table.1 RASA1-associated cytokines and physiological processes.

RASA1 in Cardiovascular Disease

Clinical statistics have confirmed the direct correlation between the loss of function or gene mutation of RASA1 and vascular diseases. This is not surprising based on the central role of RASA1 in the process of angiogenesis. Findings suggest that an appropriate level of RASA1 is beneficial for normal blood vessel development, and disturbed unbalanced RASA1 expression can cause vascular disease. RASA1 induces Nrf2-mediated oxidative stress or interacts with Krev collapsing protein 1, thereby affecting the development of blood vessels and producing vascular malformations. Studies have also shown that RASA1 mutations lead to reduced expression of MECP2 and CKDL5, which may lead to a series of vascular diseases. In addition, many studies have confirmed the direct correlation between RASA1 and myocardial fibrosis, which may be related to the upregulation of miR-21 expression caused by RASA1.

In fact, many non-cardiovascular diseases are also affected by RASA1. RASA1 may act as a downstream signaling molecule of PPARγ/miR-223 to participate in the deposition of adipocytes and lead to obesity. RASA1 can inhibit the genesis of myofibroblasts to control the course of renal fibrosis. Some diseases that are directly related to RASA1 have been listed as follows.

Table.2 RASA1-related non-cancer pathologic processes and factors.

RASA1 in Cancer

Although RASA1 is mainly involved in cardiovascular diseases, whole-genome sequencing also confirmed the direct association of RASA1 with tumorigenesis. Large-scale genome sequencing studies have identified structural mutations in RASA1 as oncogenes, and proteomic testing has shown that mutations in Ras residues 61, 13, or 12 affect intracellular guanosine triphosphate (GTP) in tumor development. The morphological exchange between GTP and GDP leads to Ras GTPase activation of RasGAP protein and Ras, modulating guanine nucleotide exchange factors.

Fig 3. RASA1 suppresses the development of renal cell carcinoma. (Zhang, 2020)

RASA1 has more than one mechanism of action in the development of cancer. The expression of RASA1 in most tumor cells is directly related to intracellular miRNA, and some tumors originate from the interaction between RASA1 and related proteins/genes. Regardless of the pathway of influence, RASA1 has become a potential genetic screening and detection target for early detection and even prevention of cancer. Proteins/genes that interact with RASA1 during tumorigenesis are listed below.

Table.3 RASA1-related cancers and factors.

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References

1. Zhang, Y.; et al. Role of RASA1 in cancer: A review and update. Oncology Reports. 2020, 44: 2386-2396.
2. Chen, Di.; et al. RASA1-driven cellular export of collagen IV is required for the development of lymphovenous and venous valves in mice. bioRxiv. 2020, 17: 953364.
3. Zhang, R.L.; et al. RASA1 inhibits the progression of renal cell carcinoma by decreasing the expression of miR-223-3p and promoting the expression of FBXW7. Bioscience Reports. 2020, 40: 4143.