WHAT IS SMALL G PROTEIN?
WHAT IS SMALL G PROTEIN?
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Small GTPases, are monomeric guanine nucleotide binding proteins related to the α subunit of heterotrimeric G proteins. All small GTPases belong to a superfamily, often named as the Ras superfamily because the founding members are encoded by human ras genes that were initially discovered as cellular homologs of the viral ras oncogene (Harvey, 1964). The Ras superfamily can be further divided into five major families: Ras, Rho, Arf, Ran and Rab.
Our interest is on Rho family, best studied for their role in promoting actin cytoskeleton reorganization, however they also play roles in cell division, cell adhesion and motility, vesicular trafficking, phagocytosis and transcriptional regulation.
MOLECULAR SWITCHES OF SMALL G PROTEIN
MOLECULAR SWITCHES OF SMALL G PROTEIN
Small RhoGTPases serve as molecular switches, regulating numerous signaling pathways by cycling between an inactive guanosine diphosphate (GDP)-bound form and an active guanosine triphosphate (GTP)-bound form. This switching is tightly regulated by three main types of proteins: GEF (Guanine Nucleotide Exchange Factors), GAP (GTPase-Activating Proteins), and GDI (Guanine Nucleotide Dissociation Inhibitors).
When in the GTP-bound state, these proteins activate downstream effector proteins, including various protein kinases, adaptor proteins, and actin-related proteins. This activation promotes diverse biological processes such as actin cytoskeleton reorganization, cell division, cell adhesion, motility, vesicular trafficking, phagocytosis, and transcriptional regulation.
CLASSIFICATION OF RHO-FAMILY SMALL G PROTEIN
CLASSIFICATION OF RHO-FAMILY SMALL G PROTEIN
In humans, there are 23 Rho-family GTPases members that can be further categorized into six major subfamilies. RhoD, RhoF and RhoH do not belong to any subfamily. The subfamilies are categorised based on their similarity in primary amino acid sequence. Among these Rho-family GTPases, the most extensively studied members are RhoA, Rac1 and Cdc42. These proteins and their subfamilies are also known as classical Rho-family GTPases.
The other Rho-family proteins are known as the non-classical or atypical Rho GTPases and include the RhoBTB, Rnd and Miro subfamilies. This classification is made based on the ability of the Rhofamily GTPases to undergo the classical GTPase cycle.The atypical Rho GTPases are not regulated by the standard GDP/GTP cycling and can be further divided into fast-cycling and GTPasedefective G proteins based on their difference in certain amino acids at position 1 2, 28, 59 and 61.
EXAMPLE OF DEREGULATION OF RHO-FAMILY SMALL G PROTEIN IN DISEASES
EXAMPLE OF DEREGULATION OF RHO-FAMILY SMALL G PROTEIN IN DISEASES
CANCER
CANCER
The deregulation of Rho family small GTPases, such as RhoA, Rac1, and Cdc42, plays a crucial role in promoting cancer aggressiveness and contributing to immune defects in tumors. These small GTPases regulate key processes like cytoskeletal dynamics, cell motility, adhesion, and cell cycle progression, which are central to tumor development and metastasis. When deregulated, they enhance cancer cell migration and invasion by modifying the actin cytoskeleton, enabling cells to breach tissue barriers and metastasize to distant organs.
PRIMARY IMMUNODEFICIENCY (PID)
PRIMARY IMMUNODEFICIENCY (PID)
Primary immunodeficiencies (PIDs) are associated with deleterious mutations of genes that encode proteins involved in actin cytoskeleton reorganisation. This deficiency affects haematopoietic cells. PID results in the defective function of immune cells, such as impaired chemokine-induced motility, receptor signalling, development and maturation.
Some of the genes mutated in PIDs are related to Rho-family small G protein such as Cdc42 and RhoH. Their contribution in PIDs may involve their main regulator, RhoGEF such as DOCK2 and DOCK8, wherein mutations may result in the impairment of small Rho GTPase activation.
PID MALIGNANCY
PID MALIGNANCY
Patients with primary immunodeficiencies (PIDs) suffer immune system dysregulation, which may progress to life-threatening illnesses. Recent therapeutic approaches solely focused on symptom relief, particularly in the case of virus infection and inflammation. After infections, malignancy is the most prevalent cause of death in PIDs, associated with mutations in genes encoding for tumour-related proteins.
Several genes are related to small RhoGTPases, including Cdc42, have been implicated in cancer. The Cdc42 C81Y mutation was found in a PID patient with lymphoproliferation, implying that a defect of Cdc42 functional activities may play a causative role in PID cancer progression by deregulating TCR signalling and homeostasis.
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