Rad: a Member of the Ras Family Overexpressed in Muscle of Type II Diabetic Humans

Abstract

To identify the gene or genes associated with insulin resistance in Type II (non-insulin-dependent) diabetes mellitus, subtraction libraries were prepared from skeletal muscle of normal and diabetic humans and screened with subtracted probes. Only one clone out of 4000 was selectively overexpressed in Type II diabetic muscle as compared to muscle of non-diabetic or Type I diabetic individuals. This clone encoded a new 29-kilodalton member of the Ras-guanosine triphosphatase superfamily and was termed Rad (Ras associated with diabetes). Messenger ribonucleic acid of Rad was expressed primarily in skeletal and cardiac muscle and was increased an average of 8.6-fold in the muscle of Type II diabetics as compared to normal individuals.

The RGK family of GTP-binding proteins: Regulators of voltage-dependent calcium channels and cytoskeleton remodeling

“…RGK proteins contain a number of non-conserved amino acids at positions important for GTP/ GDP binding and hydrolysis [3][4][5][6][7][8][9]. For example, RGK GTPases contain substitutions within the G1 motif that is involved in phosphate binding.…”

“…The residue equivalent to Gly 12 in Ras, mutation of which results in the constitutive activation of both Ras and Rho family GTPases, is altered in all RGK proteins (to Glu in Gem, Ser in Rem, and Pro in Rad and Rem2), and the highly conserved threonine residue within G1 (Thr 35 in Ras) is lacking. There are also major substitutions within the G2 and G3 domains, which function to sense GTP binding and promote conformational change within Ras family proteins during their GTP/GDP activation cycle [3][4][5][6][7][8]. All RGK proteins share a conserved DXWEX G3 motif which diverges significantly from the DTAGQ motif found in other Ras family GTPases [10].…”

“…This suggests that individual RGK proteins either associate with distinct cellular effectors (see Table 1), or perhaps that the RGK effector domain involves residues beyond the canonical switch I and switch II regions (see section 3). Despite these structural alterations, biochemical studies have revealed that all RGK proteins display micromolar affinity for GDP and GTP, and exhibit intrinsic GTPase activity [3][4][5][6][7][8][9][11][12][13].…”

“…The RGK subfamily of small GTP-binding proteins is comprised of four members, Rem (also known as Rem1 or Ges), Rem2, Rad, and Gem (mouse homolog also referred to as Kir) that exhibit conserved structural features that distinguish them from the other Ras proteins [3][4][5][6][7][8][9] (see Fig. 1).…”

“…RGK proteins also differ from one another and other Ras-related proteins within their putative effector (G2) domains, suggesting that they may interact with distinct regulatory and effector proteins. While classical GEFs and GAPs remain to be identified for the RGK GTPases (see section 2), additional methods of regulating these proteins have been identified (see sections [4][5][6]. Members of the RGK family are expressed in a tissue-specific manner and subject to both transcriptional and posttranscriptional control mechanisms that regulate protein levels in response to a diversity of environmental stimuli (see section 4).…”