RhoG is a GTPase with high sequence similarity to members of the Rac subfamily, including the regions involved in effector recognition and binding. However, RhoG does not bind to known Rac1 and Cdc42 effectors, including proteins containing a Cdc42/Rac interacting binding (CRIB) motif. Instead, RhoG interacts directly with Elmo, an upstream regulator of Rac1, in a GTP-dependent manner and forms a ternary complex with Dock180 to induce activation of Rac1 []. The RhoG-Elmo-Dock180 pathway is required for activation of Rac1 and cell spreading mediated by integrin, as well as for neurite outgrowth induced by nerve growth factor. Thus RhoG activates Rac1 through Elmo and Dock180 to control cell morphology []. RhoG has also been shown to play a role in caveolar trafficking []and has a novel role in signaling the neutrophil respiratory burst stimulated by G protein-coupled receptor (GPCR) agonists []. Most Rho proteins contain a lipid modification site at the C terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Rho proteins.
This entry represents the granule associated Rac and RHOG effector protein 1 (GARRE1), also known as KIAA0355, associates with proteins found in RNA processing bodies []. GARRE1 is found in vertebrates and has been shown to be an effector specific to the Rac subfamily of proteins [].
ARHGEF16, also called ephexin-4, acts as a guanine nucleotide exchange factor (GEF) for RhoG, activating it by exchanging bound GDP for free GTP. RhoG is a small GTPase that is a crucial regulator of Rac in migrating cells. ARHGEF16 interacts directly with the ephrin receptor EphA2 and mediates cell migration and invasion in breast cancer cells by activating RhoG [, ]. ARHGEF26, also called SGEF (SH3 domain-containing GEF), also activates RhoG. It is highly expressed in liver and may play a role in regulating membrane dynamics []. ARHGEF16 and ARHGEF26 contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology(PH), and SH3 domains. The SH3 domains of ARHGEFs play an autoinhibitory role through intramolecular interactions with a proline-rich region N-terminal to the DH domain. The SH3 domain of ARHGEF16 also binds to Elmo, and this interaction may relieve the self-inhibitory state ofARHGEF16 [].This entry represents the SH3 domains of ARHGEF16 and ARHGEF26.
DOCK family members are evolutionarily conserved guanine nucleotide exchange factors (GEFs) for Rho-family GTPases []. DOCK proteins are required during several cellular processes, such as cell motility and phagocytosis. The N-terminal SH3 domain of the DOCK proteins functions as an inhibitor of GEF, which can be relieved upon its binding to the ELMO1-3 adaptor proteins, after their binding to active RhoG at the plasma membrane [, ]. DOCK family proteins are categorised into four subfamilies based on their sequence homology: DOCK-A subfamily (DOCK1/180, 2, 5), DOCK-B subfamily (DOCK3, 4), DOCK-C subfamily (DOCK6, 7, 8), DOCK-D subfamily (DOCK9, 10, 11) [].
This entry represents the SH3 domain of DBS.DBS, also called MCF2L or OST, functions as a Rho GTPase guanine nucleotide exchange factor (RhoGEF), facilitating the exchange of GDP and GTP. It was originally isolated from a cDNA screen for sequences that cause malignant growth. It plays roles in regulating clathrin-mediated endocytosis and cell migration through its activation of Rac1 and Cdc42 [, ]. Depending on cell type, DBS can also activate RhoA and RhoG [, ]. DBS contains a Sec14-like domain [], spectrin-like repeats, a RhoGEF or Dbl homology (DH) domain, a Pleckstrin homology (PH) domain [], and an SH3 domain.
DOCK family members are evolutionarily conserved guanine nucleotide exchange factors (GEFs) for Rho-family GTPases []. DOCK proteins are required during several cellular processes, such as cell motility and phagocytosis. The N-terminal SH3 domain of the DOCK proteins functions as an inhibitor of GEF, which can be relieved upon its binding to the ELMO1-3 adaptor proteins, after their binding to active RhoG at the plasma membrane [, ]. DOCK family proteins are categorised into four subfamilies based on their sequence homology: DOCK-A subfamily (DOCK1/180, 2, 5), DOCK-B subfamily (DOCK3, 4), DOCK-C subfamily (DOCK6, 7, 8), DOCK-D subfamily (DOCK9, 10, 11) []. This entry represents DOCK9 (also known as Zizimin). DOCK9 and DOCK11 activate Cdc42 [, ].
DOCK family members are evolutionarily conserved guanine nucleotide exchange factors (GEFs) for Rho-family GTPases []. DOCK proteins are required during several cellular processes, such as cell motility and phagocytosis. The N-terminal SH3 domain of the DOCK proteins functions as an inhibitor of GEF, which can be relieved upon its binding to the ELMO1-3 adaptor proteins, after their binding to active RhoG at the plasma membrane [, ]. DOCK family proteins are categorised into four subfamilies based on their sequence homology: DOCK-A subfamily (DOCK1/180, 2, 5), DOCK-B subfamily (DOCK3, 4), DOCK-C subfamily (DOCK6, 7, 8), DOCK-D subfamily (DOCK9, 10, 11) []. This entry represents DOCK2 (dedicator of cytokinesis 2). DOCK2 is involved in cytoskeletal rearrangements required for lymphocyte migration in response of chemokines. It activates RAC1 and RAC2, but not CDC42, by functioning as a guanine nucleotide exchange factor (GEF), which exchanges bound GDP for free GTP. It may also participate in IL2 transcriptional activation via the activation of RAC2 [].
DOCK family members are evolutionarily conserved guanine nucleotide exchange factors (GEFs) for Rho-family GTPases []. DOCK proteins are required during several cellular processes, such as cell motility and phagocytosis. The N-terminal SH3 domain of the DOCK proteins functions as an inhibitor of GEF, which can be relieved upon its binding to the ELMO1-3 adaptor proteins, after their binding to active RhoG at the plasma membrane [, ]. DOCK family proteins are categorised into four subfamilies based on their sequence homology: DOCK-A subfamily (DOCK1/180, 2, 5), DOCK-B subfamily (DOCK3, 4), DOCK-C subfamily (DOCK6, 7, 8), DOCK-D subfamily (DOCK9, 10, 11) []. This entry represents DOCK3. DOCK3 is linked to Alzheimer disease due to its interaction with presenilin proteins and ability to stimulate Tau/MAPT phosphorylation [].
This entry includes DOCK5, which, along with DOCK1, mediates CRK/CRKL regulation of epithelial and endothelial cell spreading and migration on collagen IV [].DOCK family members are evolutionarily conserved guanine nucleotide exchange factors (GEFs) for Rho-family GTPases []. DOCK proteins are required during several cellular processes, such as cell motility and phagocytosis. The N-terminal SH3 domain of the DOCK proteins functions as an inhibitor of GEF, which can be relieved upon its binding to the ELMO1-3 adaptor proteins, after their binding to active RhoG at the plasma membrane [, ]. DOCK family proteins are categorised into four subfamilies based on their sequence homology: DOCK-A subfamily (DOCK1/180, 2, 5), DOCK-B subfamily (DOCK3, 4), DOCK-C subfamily (DOCK6, 7, 8), DOCK-D subfamily (DOCK9, 10, 11) [].
DOCK family members are evolutionarily conserved guanine nucleotide exchange factors (GEFs) for Rho-family GTPases []. DOCK proteins are required during several cellular processes, such as cell motility and phagocytosis. The N-terminal SH3 domain of the DOCK proteins functions as an inhibitor of GEF, which can be relieved upon its binding to the ELMO1-3 adaptor proteins, after their binding to active RhoG at the plasma membrane [, ]. DOCK family proteins are categorised into four subfamilies based on their sequence homology: DOCK-A subfamily (DOCK1/180, 2, 5), DOCK-B subfamily (DOCK3, 4), DOCK-C subfamily (DOCK6, 7, 8), DOCK-D subfamily (DOCK9, 10, 11) []. This entry represents DOCK4. DOCK4 plays a critical role in mediating TGF-beta's prometastatic effects in lungcancer [].
VAV2 is widely expressed and functions as a guanine nucleotide exchange factor (GEF) for RhoA, RhoB and RhoG and also activates Rac1 and Cdc42 []. It is implicated in many cellular and physiological functions including blood pressure control, eye development, neurite outgrowth and branching, EGFR endocytosis and degradation, and cell cluster morphology, among others [, , , , ]. It has been reported to associate with Nek3. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The SH3 domain of VAV is involved in the localization of proteins to specific sites within the cell, by interacting with proline-rich sequences within target proteins [, , ].This entry represents the second SH3 domain of VAV2.
VAV2 is widely expressed and functions as a guanine nucleotide exchange factor (GEF) for RhoA, RhoB and RhoG and also activates Rac1 and Cdc42 []. It is implicated in many cellular and physiological functions including blood pressure control, eye development, neurite outgrowth and branching, EGFR endocytosis and degradation, and cell cluster morphology, among others [, , , , ]. It has been reported to associate with Nek3. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The SH3 domain of VAV is involved in the localization of proteins to specific sites within the cell, by interacting with proline-rich sequences within target proteins [, , ].This entry represents the first SH3 domain of VAV2.
DOCK family members are evolutionarily conserved guanine nucleotide exchange factors (GEFs) for Rho-family GTPases []. DOCK proteins are required during several cellular processes, such as cell motility and phagocytosis. The N-terminal SH3 domain of the DOCK proteins functions as an inhibitor of GEF, which can be relieved upon its binding to the ELMO1-3 adaptor proteins, after their binding to active RhoG at the plasma membrane [, ]. DOCK family proteins are categorised into four subfamilies based on their sequence homology: DOCK-A subfamily (DOCK1/180, 2, 5), DOCK-B subfamily (DOCK3, 4), DOCK-C subfamily (DOCK6, 7, 8), DOCK-D subfamily (DOCK9, 10, 11) []. This entry represents the SH3 domain found in DOCK3, which has been linked to Alzheimer's disease due to its interaction with presenilin proteins and ability to stimulate Tau/MAPT phosphorylation [].
DOCK family members are evolutionarily conserved guanine nucleotide exchange factors (GEFs) for Rho-family GTPases []. DOCK proteins are required during several cellular processes, such as cell motility and phagocytosis. The N-terminal SH3 domain of the DOCK proteins functions as an inhibitor of GEF, which can be relieved upon its binding to the ELMO1-3 adaptor proteins, after their binding to active RhoG at the plasma membrane [, ]. DOCK family proteins are categorised into four subfamilies based on their sequence homology: DOCK-A subfamily (DOCK1/180, 2, 5), DOCK-B subfamily (DOCK3, 4), DOCK-C subfamily (DOCK6, 7, 8), DOCK-D subfamily (DOCK9, 10, 11) []. This entry represents the SH3 domain found in DOCK4. DOCK4 regulates dendritic spine formation and has been linked to autism, dyslexia, and schizophrenia []. It also plays a critical role in mediating TGF-beta's prometastatic effects in lung cancer [].
This entry represents the PH domain of guanine nucleotide exchange factor DBS. The DBS PH domain participates in binding to both the Cdc42 and RhoA GTPases []. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner [].DBS, also called MCF2L or OST, functions as a Rho GTPase guanine nucleotide exchange factor (RhoGEF), facilitating the exchange of GDP and GTP. It was originally isolated from a cDNA screen for sequences that cause malignant growth. It plays roles in regulating clathrin-mediated endocytosis and cell migration through its activation of Rac1 and Cdc42 [, ]. Depending on cell type, DBS can also activate RhoA and RhoG [, ]. DBS contains a Sec14-like domain [], spectrin-like repeats, a RhoGEF or Dbl homology (DH) domain, a Pleckstrin homology (PH) domain [], and an SH3 domain.
DOCK family members are evolutionarily conserved guanine nucleotide exchange factors (GEFs) for Rho-family GTPases []. DOCK proteins are required during several cellular processes, such as cell motility and phagocytosis. The N-terminal SH3 domain of the DOCK proteins functions as an inhibitor of GEF, which can be relieved upon its binding to the ELMO1-3 adaptor proteins, after their binding to active RhoG at the plasma membrane [, ]. DOCK family proteins are categorised into four subfamilies based on their sequence homology: DOCK-A subfamily (DOCK1/180, 2, 5), DOCK-B subfamily (DOCK3, 4), DOCK-C subfamily (DOCK6, 7, 8), DOCK-D subfamily (DOCK9, 10, 11) []. This entry represents the N-terminal domain of the DOCK-C subfamily (DOCK 6, 7, 8) and DOCK-D subfamily (DOCK 9, 10, 11).
DOCK family members are evolutionarily conserved guanine nucleotide exchange factors (GEFs) for Rho-family GTPases []. DOCK proteins are required during several cellular processes, such as cell motility and phagocytosis. The N-terminal SH3 domain of the DOCK proteins functions as an inhibitor of GEF, which can be relieved upon its binding to the ELMO1-3 adaptor proteins, after their binding to active RhoG at the plasma membrane [, ]. DOCK family proteins are categorised into four subfamilies based on their sequence homology: DOCK-A subfamily (DOCK1/180, 2, 5), DOCK-B subfamily (DOCK3, 4), DOCK-C subfamily (DOCK6, 7, 8), DOCK-D subfamily (DOCK9, 10, 11) []. This entry represents the C2 domain found in the Dock-C members. In addition to the C2 domain (also known as DHR-1 domain) and the DHR-2 domain, Dock-C members contain a functionally uncharacterised domain upstream of the C2 domain. DHR-2 has the catalytic activity for Rac and/or Cdc42, but is structurally unrelated to the DH domain. The C2/DHR-1 domains of Dock1 (also known as Dock180) and Dock4 have been shown to bind phosphatidylinositol-3, 4, 5-triphosphate (PtdIns(3,4,5)P3) [, , ].
DOCK family members are evolutionarily conserved guanine nucleotide exchange factors (GEFs) for Rho-family GTPases []. DOCK proteins are required during several cellular processes, such as cell motility and phagocytosis. The N-terminal SH3 domain of the DOCK proteins functions as an inhibitor of GEF, which can be relieved upon its binding to the ELMO1-3 adaptor proteins, after their binding to active RhoG at the plasma membrane [, ]. DOCK family proteins are categorised into four subfamilies based on their sequence homology: DOCK-A subfamily (DOCK1/180, 2, 5), DOCK-B subfamily (DOCK3, 4), DOCK-C subfamily (DOCK6, 7, 8), DOCK-D subfamily (DOCK9, 10, 11) []. This entry represents the C2 domain of the Dock-D members. In addition to the C2 domain (also known as the DHR-1 domain) and the DHR-2, Dock-D members contain a functionally uncharacterised domain and a PH domain upstream of the C2 domain. DHR-2 has the catalytic activity for Rac and/or Cdc42, but is structurally unrelated to the DH domain. The C2/DHR-1 domains of Dock1 (also known as Dock180) and Dock4 have been shown to bind phosphatidylinositol-3, 4, 5-triphosphate (PtdIns(3,4,5)P3). The PH domain broadly binds to phospholipids and is thought to be involved in targeting the plasma membrane [, , ].
DOCK family members are evolutionarily conserved guanine nucleotide exchange factors (GEFs) for Rho-family GTPases []. DOCK proteins are required during several cellular processes, such as cell motility and phagocytosis. The N-terminal SH3 domain of the DOCK proteins functions as an inhibitor of GEF, which can be relieved upon its binding to the ELMO1-3 adaptor proteins, after their binding to active RhoG at the plasma membrane [, ]. DOCK family proteins are categorised into four subfamilies based on their sequence homology: DOCK-A subfamily (DOCK1/180, 2, 5), DOCK-B subfamily (DOCK3, 4), DOCK-C subfamily (DOCK6, 7, 8), DOCK-D subfamily (DOCK9, 10, 11) []. This entry represents the C2 domain of the Dock-B members. Most of these members have been shown to be GEFs specific for Rac, although Dock4 has also been shown to interact indirectly with the Ras family GTPase Rap1, probably through Rap regulatory proteins. In addition to the C2 domain (also known as DHR-1 domain) and the DHR-2 domain, Dock-B members contain a SH3 domain upstream of the C2 domain and a proline-rich region downstream. DHR-2 has the catalytic activity for Rac and/or Cdc42, but is structurally unrelated to the DH domain. The C2/DHR-1 domains of Dock1 (also known as Dock180) and Dock4 have been shown to bind phosphatidylinositol-3, 4, 5-triphosphate (PtdIns(3,4,5)P3)[, , ].
This entry includes a group of RhoGEFs, including Kalirin and TRIO from mammals. Kalirin and TRIO are encoded by separate genes in mammals and by a single one in invertebrates. Kalirin and TRIO share the same complex multidomain structure and display several splice variants. They are implicated in secretory granule (SG) maturation and exocytosis [, ]. The longest Kalirin and TRIO proteins have a Sec14 domain, a stretch of spectrin repeats, a RhoGEF(DH)/PH cassette (also called GEF1), an SH3 domain, a second RhoGEF(DH)/PH cassette (also called GEF2), a second SH3 domain, Ig/FNIII domains, and a kinase domain. The first RhoGEF(DH)/PH cassette catalyzes exchange on Rac1 and RhoG while the second RhoGEF(DH)/PH cassette is specific for RhoA. Kalirin and TRIO are closely related to p63RhoGEF and have PH domains of similar function. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner [, ].Triple functional domain protein (TRIO) contains a protein kinase domain and two guanine nucleotide exchange factor (GEF) domains []. These functional domains suggest that it may play a role in signalling pathways controlling cell proliferation []. TRIO may form a complex with LAR transmembrane protein tyrosine phosphatase (PT-Pase), which localises to the ends of focal adhesions and plays an important part in coordinating cell-matrix and cytoskeletal rearrangements necessary for cell migration []. Its expression is associated with invasive tumor growth and rapid tumor cell proliferation in urinary bladder cancer [].Kalirin () promotes the exchange of GDP by GTP and stimulates the activity of specific Rho GTPases []. There are several Kalirin isoforms in humans and mice. Each Kalirin isoform is composed of a unique collection of domains and may have different functions []. In rat, isoforms 1 and 7 are necessary for neuronal development and axonal outgrowth, while isoform 6 is required for dendritic spine formation []. In humans, the major isoform of Kalirin in the adult brain is Kalirin-7, which plays a critical role in spine formation/synaptic plasticity. Kalirin-7 has been linked to neuropsychiatric and neurological diseases such as Alzheimer's, Huntingtin's, ischemic stroke, schizophrenia, depression, and cocaine addiction [, , ].
