Rap1

Last updated
RAP1A,
member of RAS oncogene family
Identifiers
Symbol RAP1A
NCBI gene 5906
HGNC 9855
OMIM 179520
RefSeq NM_002884
UniProt P62834
Other data
Locus Chr. 1 p13.3
RAP1B,
member of RAS oncogene family
Identifiers
Symbol RAP1B
NCBI gene 5908
HGNC 9857
OMIM 179530
RefSeq NM_001010942
UniProt P61224
Other data
Locus Chr. 12 q14

Rap1 (Ras-proximate-1 or Ras-related protein 1) is a small GTPase, which are small cytosolic proteins that act like cellular switches and are vital for effective signal transduction. [1] There are two isoforms of the Rap1 protein, each encoded by a separate gene, RAP1A and RAP1B. Rap1 belongs to Ras-related protein family.

Contents

GTPases are inactive when in their GDP-bound form, and become active when they bind to GTP. GTPase activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs) regulate small GTPases, with GAPs promoting the GDP-bound (inactive) form, and GEFs promoting the GTP-bound (active) form. When bound to GTP, small GTPases regulate myriad cellular processes. These proteins are divided into families depending on their protein structure, and the most well studied is the Ras superfamily, of which Rap1 is a member. Whereas Ras is known for its role in cell proliferation and survival, Rap1 is predominantly involved in cell adhesion and cell junction formation. Ras and Rap are regulated by different sets of guanine nucleotide exchange factors and GTPase-activating proteins, thus providing one level of specificity. [2]

Effectors

RAPL

The identification of Rap1 effector proteins has provided important insights into mechanisms by which Rap1 regulates T-cell receptor (TCR) signaling to integrins. A constitutively active Rap1 construct, Rap1G12V, was used as a bait in a yeast two-hybrid screen to identify RAPL as a Rap1-binding protein. [3]

Overexpression of RAPL enhances LFA-1 clustering and adhesion, and RAPL-deficient lymphocytes and dendritic cells exhibit impaired adhesion and migration. [4] RAPL is also an integrin-associated protein as RAPL polarizes to the immunological synapse following antigen stimulation of T cells, colocalizes with LFA-1 following TCR or chemokine stimulation, and co-immunoprecipitates with LFA-1 in a Rap1-dependent manner (108). This interaction between RAPL and LFA-1 is dependent on lysine residues at positions 1097 and 1099 in the juxtamembrane region of the αL-subunit cytoplasmic domain. This is a functionally significant region of the αL cytoplasmic domain as deletion of the adjacent GFFKR motif results in a constitutively active LFA-1 integrin (124, 125). While lysines 1097 and 1099 are critical for Rap1-dependent activation of LFA-1, the β2-subunit cytoplasmic domain appears to be dispensable for activation of LFA-1 by Rap1 (126). Mutation of these lysine residues to alanine impairs the ability of LFA-1 to redistribute to the leading edge induced by Rap1 activation or overexpression of RAPL. Because RAPL localizes to the leading edge properly in cells expressing this mutant LFA-1, this finding suggests that RAPL may play a critical role in localizing LFA-1 to discrete regions of the plasma membrane. In T-cells, the immune cell adaptor SKAP1 couples the TCR to the formation of a complex between Rap1 and RapL for T-cell adhesion. [5]

Mst1

The serine–threonine kinase Mst1, a member of a family of kinases homologous to the Ste20 kinase in yeast, [6] has recently been identified as a RAPL effector. [7] TCR-mediated activation of Mst1 is dependent on RAPL, and TCR-mediated adhesion to ICAM-1 and antigen-dependent conjugate formation are impaired following RNAi-mediated knockdown of Mst1 expression. Although Rap1 and RAPL have been shown to regulate both LFA-1 affinity and clustering, overexpression of Mst1 only enhances LFA-1 clustering. This finding suggests that LFA-1 clustering is critical for TCR signaling to integrins that is mediated by Rap1. It also implies the existence of Mst1-independent mechanisms by which Rap1 regulates LFA-1 affinity.

PKD

A striking feature of Rap1 and the Rap1-associated signaling proteins PKD, RAPL, and Mst1 is their localization to membranes where integrins are found. This provides a mechanism by which Rap1 can act directly on integrins and modulate integrin affinity and/or clustering. PKD, RAPL, and Mst1 have also all been proposed to play a role in movement of receptors to the plasma membrane. PKD-dependent regulation of vesicular transport requires PKD kinase activity, while PKD-dependent regulation of TCR signaling to integrins does not appear to require PKD kinase activity. Thus, PKD may play a distinct role in regulating Rap1-dependent integrin regulation. For example, the PKD-dependent association of Rap1 with C3G suggests that PKD may be critical for localizing Rap1 not only with integrins but also with Rap1 GEFs. The PKD–Rap1 interaction may thus be central to the subsequent activation of Rap1 and triggering of downstream effectors such as RAPL and Mst1.

RIAM

An additional Rap1 effector provides a link between Rap1 and the actin cytoskeleton. RIAM (Rap1–GTP-interacting adapter molecule) is a broadly expressed adaptor protein that contains an RA (Ras association)-like domain, a PH domain, and several proline-rich sequences. Like RAPL, RIAM interacts preferentially with active Rap1, and overexpression of RIAM enhances integrin-mediated adhesion. In addition, knockdown of RIAM inhibits adhesion induced by active Rap1 and inhibits the localization of active Rap1 at the plasma membrane. The ability of RIAM to associate with profilin, Ena/VASP proteins, and talin suggests that RIAM promotes Rap1-dependent integrin activation through effects on the actin cytoskeleton, particularly the interaction of talin with integrin cytoplasmic tails. Given the known role of talin in regulating integrin affinity, RIAM may provide an Mst1-independent mechanism by which Rap1 regulates integrin affinity.

Related Research Articles

Ras GTPase GTP-binding proteins functioning on cell-cycle regulation

Ras is a family of related proteins which is expressed in all animal cell lineages and organs. All Ras protein family members belong to a class of protein called small GTPase, and are involved in transmitting signals within cells. Ras is the prototypical member of the Ras superfamily of proteins, which are all related in 3D structure and regulate diverse cell behaviours.

T-cell receptor Protein complex on the surface of T cells that recognises antigens

The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The binding between TCR and antigen peptides is of relatively low affinity and is degenerate: that is, many TCRs recognize the same antigen peptide and many antigen peptides are recognized by the same TCR.

Biological crosstalk refers to instances in which one or more components of one signal transduction pathway affects another. This can be achieved through a number of ways with the most common form being crosstalk between proteins of signaling cascades. In these signal transduction pathways, there are often shared components that can interact with either pathway. A more complex instance of crosstalk can be observed with transmembrane crosstalk between the extracellular matrix (ECM) and the cytoskeleton.

ICAM-1

ICAM-1 also known as CD54 is a protein that in humans is encoded by the ICAM1 gene. This gene encodes a cell surface glycoprotein which is typically expressed on endothelial cells and cells of the immune system. It binds to integrins of type CD11a / CD18, or CD11b / CD18 and is also exploited by rhinovirus as a receptor for entry into respiratory epithelium.

Immunological synapse

In immunology, an immunological synapse is the interface between an antigen-presenting cell or target cell and a lymphocyte such as a T/B cell or Natural Killer cell. The interface was originally named after the neuronal synapse, with which it shares the main structural pattern. An immunological synapse consists of molecules involved in T cell activation, which compose typical patterns—activation clusters. Immunological synapses are the subject of much ongoing research.

Lymphocyte function-associated antigen 1 (LFA-1) is an integrin found on lymphocytes and other leukocytes. LFA-1 plays a key role in emigration, which is the process by which leukocytes leave the bloodstream to enter the tissues. LFA-1 also mediates firm arrest of leukocytes. Additionally, LFA-1 is involved in the process of cytotoxic T cell mediated killing as well as antibody mediated killing by granulocytes and monocytes. As of 2007, LFA-1 has 6 known ligands: ICAM-1, ICAM-2, ICAM-3, ICAM-4, ICAM-5, and JAM-A. LFA-1/ICAM-1 interactions have recently been shown to stimulate signaling pathways that influence T cell differentiation. LFA-1 belongs to the integrin superfamily of adhesion molecules.

CDC42 Protein-coding gene in the species Homo sapiens

Cell division control protein 42 homolog, also known as Cdc42, is a protein involved in regulation of the cell cycle. It was originally identified in S. cerevisiae (yeast) as a mediator of cell division, and is now known to influence a variety of signaling events and cellular processes in a variety of organisms from yeast to mammals.

Transforming protein RhoA Protein-coding gene in the species Homo sapiens

Transforming protein RhoA, also known as Ras homolog family member A (RhoA), is a small GTPase protein in the Rho family of GTPases that in humans is encoded by the RHOA gene. While the effects of RhoA activity are not all well known, it is primarily associated with cytoskeleton regulation, mostly actin stress fibers formation and actomyosin contractility. It acts upon several effectors. Among them, ROCK1 and DIAPH1 are the best described. RhoA, and the other Rho GTPases, are part of a larger family of related proteins known as the Ras superfamily, a family of proteins involved in the regulation and timing of cell division. RhoA is one of the oldest Rho GTPases, with homologues present in the genomes since 1.5 billion years. As a consequence, RhoA is somehow involved in many cellular processes which emerged throughout evolution. RhoA specifically is regarded as a prominent regulatory factor in other functions such as the regulation of cytoskeletal dynamics, transcription, cell cycle progression and cell transformation.

RAS p21 protein activator 1

RAS p21 protein activator 1 or RasGAP, also known as RASA1, is a 120-kDa cytosolic human protein that provides two principal activities:

PTK2B

Protein tyrosine kinase 2 beta is an enzyme that in humans is encoded by the PTK2B gene.

RAP1GAP

Rap1 GTPase-activating protein 1 is an enzyme that in humans is encoded by the RAP1GAP gene.

RHEB

RHEB also known as Ras homolog enriched in brain (RHEB) is a GTP-binding protein that is ubiquitously expressed in humans and other mammals. The protein is largely involved in the mTOR pathway and the regulation of the cell cycle.

RAC3

Ras-related C3 botulinum toxin substrate 3 (Rac3) is a G protein that in humans is encoded by the RAC3 gene. It is an important component of intracellular signalling pathways. Rac3 is a member of the Rac subfamily of the Rho family of small G proteins. Members of this superfamily appear to regulate a diverse array of cellular events, including the control of cell growth, cytoskeletal reorganization, and the activation of protein kinases.

NEDD9

Neural precursor cell expressed developmentally down-regulated protein 9 (NEDD-9) is a protein that in humans is encoded by the NEDD9 gene. NEDD-9 is also known as enhancer of filamentation 1 (EF1), CRK-associated substrate-related protein (CAS-L), and Cas scaffolding protein family member 2 (CASS2). An important paralog of this gene is BCAR1.

RASSF5

Ras association domain-containing protein 5 is a protein that in humans is encoded by the RASSF5 or F5 gene.

ARHGAP5

Rho GTPase-activating protein 5 is an enzyme that in humans is encoded by the ARHGAP5 gene.

SKAP1

Src kinase-associated phosphoprotein 1 is an adapter protein that in humans is encoded by the SKAP1 gene.

MRAS

Ras-related protein M-Ras, also known as muscle RAS oncogene homolog and R-Ras3, is a protein that in humans is encoded by the MRAS gene on chromosome 3. It is ubiquitously expressed in many tissues and cell types. This protein functions as a signal transducer for a wide variety of signaling pathways, including those promoting neural and bone formation as well as tumor growth. The MRAS gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.

APBB1IP

Amyloid beta A4 precursor protein-binding family B member 1-interacting protein (APBB1IP), also known as APBB1-interacting protein 1 or Rap1-GTP-interacting adapter molecule (RIAM) is a protein that in humans is encoded by the APBB1IP gene.

Alan Hall FRS was a British cell biologist and a biology professor at the Sloan-Kettering Institute, where he was chair of the Cell Biology program. Hall was elected a Fellow of the Royal Society in 1999.

References

  1. ↑ Burbach BJ, Medeiros RB, Mueller KL, Y. Shimizu (August 2007). "T-cell receptor signaling to integrins". Immunol. Rev. 218: 65–81. doi:10.1111/j.1600-065X.2007.00527.x. PMID   17624944. S2CID   32675702.CS1 maint: multiple names: authors list (link)
  2. ↑ Raaijmakers JH, Bos JL (April 2009). "Specificity in Ras and Rap Signaling". J. Biol. Chem. 284 (17): 10995–9. doi:10.1074/jbc.R800061200. PMC   2670103 . PMID   19091745.
  3. ↑ Katagiri K, Maeda A, Shimonaka M, Kinashi T (August 2003). "RAPL, a Rap1-binding molecule that mediates Rap1-induced adhesion through spatial regulation of LFA-1". Nat. Immunol. 4 (8): 741–8. doi:10.1038/ni950. PMID   12845325. S2CID   10588415.
  4. ↑ Katagiri K, Ohnishi N, Kabashima K, Iyoda T, Takeda N, Shinkai Y, Inaba K, Kinashi T (October 2004). "Crucial functions of the Rap1 effector molecule RAPL in lymphocyte and dendritic cell trafficking". Nat. Immunol. 5 (10): 1045–51. doi:10.1038/ni1111. PMID   15361866. S2CID   32013660.
  5. ↑ Raab M, Wang H, Lu Y, Smith X, Wu Z, Strebhardt K, Ladbury JE, Rudd CE (March 2010). "T cell receptor "inside-out" pathway via signaling module SKAP1-RapL regulates T cell motility and interactions in lymph nodes". Immunity. 32 (4): 541–56. doi:10.1016/j.immuni.2010.03.007. PMC   3812847 . PMID   20346707.
  6. ↑ Creasy CL, Chernoff J (December 1995). "Cloning and characterization of a member of the MST subfamily of Ste20-like kinases". Gene. 167 (1–2): 303–6. doi:10.1016/0378-1119(95)00653-2. PMID   8566796.
  7. ↑ Katagiri K, Imamura M, Kinashi T (September 2006). "Spatiotemporal regulation of the kinase Mst1 by binding protein RAPL is critical for lymphocyte polarity and adhesion". Nat. Immunol. 7 (9): 919–28. doi:10.1038/ni1374. PMID   16892067. S2CID   12337748.
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