Ras superfamily members

Kavelaars A, Jeurissen F, von Frijtag Drabbe Kunzel J, Herman van Roijen J, Rijkers GT, Heijnen CJ (1993) Substance P induces a rise in intracellular calcium concentration in human T lymphocytes in vitro evidence of a receptor-independent mechanism. J Neuroimmunol 42 61-70 Kemppainen RJ, Behrend EN (1998) Dexamethasone rapidly induces a novel ras superfamily member-related gene in AtT-20 cells. J Biol Chem 273 3129-3131... 

Most of the biological functions of the members of the Ras superfamily are linked to the cytoplasmic side of the cell membrane, where specific signals are received and transmitted further. Accordingly, Ras superfamily members contain structural features that mediate membrane association and serve as lipid anchors (see Section 3.7). Prenylation, palmitoylation and myristoylation are post-translational modifications frequently found on Ras superfamily members. 

The transition from inactive GDP state to active GTP state may be accelerated by proteins that cause the bound GDP to dissociate. The guanine nucleotide exchange factors (GEFs) play an essential role in the function of the Ras superfamily members. 

S-acylated proteins include many GTP-binding regulatory proteins (G proteins), including most a subunits of heterotrimeric G-proteins and also many members of the Ras superfamily of monomeric G proteins, a number of G protein-coupled receptors, several nonreceptor tyrosine kinases, and a number of other signaling molecules, -acylation is posttranslational and reversible, a property that allows the cell to control... 

MAPK kinase (MAPKK). MAPK kinase itself is activated by phosphorylation by still another protein kinase, termed MAPK kinase kinase (MAPKKK). MAPK kinase kinase is activated upon interaction with a member of the Ras superfamily of small G proteins, which are bound to the plasma membrane (see Ch. 19). The exact mechanism of activation remains unknown, but it is believed that Ras and related proteins, in the activated GTP-bound form, can bind MAPK kinase kinase and thereby draw the kinase to the plasmalemma, where it is activated by as yet unknown factors, perhaps even an additional kinase, MAPK kinase kinase kinase (MAPKKKK). The mechanism governing the activation of Ras and related proteins by extracellular signals is quite complex and involves numerous Tinker proteins, for example She, Grb and Sos, that couple Ras to a variety of plasmalemma-associated growth factor-protein tyrosine kinase receptors (see Chs 20,24 and 27). 

All proteins of the Ras superfamily (Table 1) - with the exception of the Ran protein - undergo a posttranslational modification which introduces at least one hydrophobic modification. These lipid anchors qualify the members of the Ras family as peripheral membrane proteins, which stick into membrane structures from the cytoplasmic side only. 

The isoprenoid modification can be found, among others, on the Ras protein and other members of the Ras superfamily (see chapter 9), as well as with the a-subunit of G-protein (see chapter 5). The Pycomplex of G-proteins is also associated with the membrane via geranylation. 

Following the discovery of the Ras protein, it was quickly estabhshed that Ras proteins are a family within a large superfamily, known today as the Ras superfamily of monomeric GTPases. Hie members of the superfamUy of Ras proteins are regulatory GTPases of 16-25 kDa, which are active as monomers. 

The Ras GTP-mediated activation of P13-kinase links the Ras pathway with fimcti-ons of the Rho/Rac proteins. Members of this protein family within the Ras superfamily control formation of the cytoskeleton. The exact nature of the linkage with the Ras/PI3-kinase signal conduction to the Rac proteins is unknown. There is evidence that the product of the P13-kinase, Ptd-lns(3,4,5)P3, binds to the PH domain of the Vav protein and activates the latter. The Vav protein functions as a nucleotide exchange factor for the Rac GTPase (Han et al., 1998). The observation that activation of the Ras pathway is accompanied by reorganization of the cytoskeleton is in agreement with these findings. 

There are also links to other members of the Ras superfamily, such as the Ral protein and the Rho/Rac proteins. The latter are involved in reorganization of the actin cytoskeleton. Transformation of cells with oncogenic Ras mutants is associated with reorganization of the actin cytoskeleton and it is assumed that this effect is due to coupling of the Ras pathways with the fimction of Rho/Rac proteins. 

The catalytic glutamine at position 204 in Gail is a conserved feature in all functional Ga proteins, and in most members of the Ras superfamily (residue 61 in Ras). Mutations of this residue in Ga and Ras abolish GTPase activity, are constitutively active, and contribute to cellular transformation (Barbacid, 1987 Bourne et aL, 1991 Gilman, 1987). Further, GTPase activity of the... 

Membrane attachment of Ras requires covalent addition of lipids. Virtually all members of the Ras superfamily are prenylated.io Farnesylation is essential. Defects in lipid modification make Ras non-functional. A 15-carbon farnesyl or 20-carbon geranyl-geranyl chain is attached to a cysteine in the COOH-terminus of Ras. The linkage is by a thioether bond and irreversible, and therefore not a point of regulatory control, n ... 

A somewhat similar zinc site is seen in one of the ADP ribosylation factors (ARFs), which are members of the Ras superfamily of GTP-binding proteins. Sequences of ARF-GAP domains show no recognizable similarity to those of... 

The superfamily of GTPases, with over 100 members, is subdivided according to sequence homologies, molecular weight and subunit structure into further (super)families. These are the families of the heterotrimeric G proteins, the Ras superfamily of small GTPases and the family of initiation and elongation factors (Fig. 5.15). 

RhoB, which is a GTP-binding protein member of the ras superfamily may also play a role in neural crest cell delamination as it is selectively expressed in the dorsal neural tube and transiently expressed by the neural crest. RhoB expression is induced by... 

Many other proteins closely related to ras are now known and are considered as members of the ras superfamily which numbers >100 members. Within this superfamily are several subgroups, with Ras being joined by the Ran/Rac, Ypt/Rab and Rho proteins. The cellular functions of these proteins are exceedingly diverse including such processes as vesicular trafficking, cytoskeletal control and NADPH oxidase function. Clearly, such important proteins have plant homologues which will be discussed later. 

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