PH domain: the first anniversary

Gibson, Toby J.; Hyvönen, Marko; Musacchio, Andrea; Saraste, Matti; Birney, Ewan

doi:10.1016/0968-0004(94)90108-2

Cited by 325 publications

(258 citation statements)

References 25 publications

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“…These structures exhibit a common globular fold that consists of seven anti-parallel b strands and an a helix (Gibson et al, 1994;Lemmon et al, 1996). The b strands are arranged into two sheets that are positioned approximately orthogonal to each other while the a helix caps o an opening between the sheets, thus enclosing a stable hydrophobic core.…”

Section: A Structural Model Of the Akt Ph Domainmentioning

confidence: 99%

Akt activation by growth factors is a multiple-step process: the role of the PH domain

et al. 1998

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The protein kinase encoded by the Akt proto-oncogene is activated by phospholipid binding, membrane translocation and phosphorylation. To address the relative roles of these mechanisms of Akt activation, we have employed a combination of genetic and pharmacological approaches. Transient transfection of NIH3T3 cells with wild-type Akt, pleckstrin homology (PH) domain mutants, generated on the basis of a PH domain structural model, and phosphorylation site Akt mutants provided evidence for a model of Akt activation consisting of three sequential steps: (1) a PH domain-dependent, growth factor-independent step, marked by constitutive phosphorylation of threonine 450 (T450) and perhaps serine 124 (S124), that renders the protein responsive to subsequent activation events; (2) a growth factor-induced, PI3-K-dependent membrane-translocation step; and (3) a PI3-K-dependent step, characterized by phosphorylation at T308 and S473, that occurs in the cell membrane and is required for activation. When forced to translocate to the membrane, wild-type Akt and PH domain Akt mutants that are defective in the ®rst step become constitutively active, suggesting that the purpose of this step is to prepare the protein for membrane translocation. Both growth factor stimulation and forced membrane translocation, however, failed to activate a T308A mutant. This, combined with the ®nding that T308D/S473D double mutant is constitutively active, suggests that the purpose of the three-step process of Akt activation is the phosphorylation of the protein at T308 and S473. The proposed model provides a framework for a comprehensive understanding of the temporal and spatial requirements for Akt activation by growth factors.

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Section: A Structural Model Of the Akt Ph Domainmentioning

confidence: 99%

Akt activation by growth factors is a multiple-step process: the role of the PH domain

et al. 1998

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“…by dashes and a 83 aa insertion in p160 R°cK is indicated. Homologies between these three proteins are boxed, related residues being grouped as follows: EDQN; RKH; LVI; FYW; ST; GA. A consensus sequence for PH domains [23] is shown below; residues from this sequence conserved in at least 50% of the 71 reported PH domains [23,26] are marked by stars. The six PH sub-domains are indicated.…”

Section: Rho and Racl Interact Directly With Citron In Vitromentioning

confidence: 99%

A novel partner for the GTP‐bound forms of rho and rac

et al. 1995

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Ahstract Using the yeast two hybrid system and overlay assays we identified a putative rholrac effector, citron, which interacts with the GTP-bound forms of rho and racl, but not with cdc42. Extensive homologies to known proteins were not observed. This 183 kDa protein contains a C~H2 zinc finger, a PH domain, and a long coiled-coil forming region including 4 leucine zippers and the rholrac binding site. We recently identified three others putative rho effeetors characterized by a common rho binding motif. Citron does not share this motif and displays a distinctive protein organization, thus defining a separate class of rho partners.

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“…With a sequence of 912 amino acids PKC~t is larger than the other PKCs. It contains a hydrophobic domain in the N-terminal region and a pleckstrin homology (PH) domain [7] which is currently discussed as a potential region for protein/protein interactions or lipid binding [8,9]. PKC/a does not contain a region homologous to pseudosubstrate regions of other PKC family members.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of protein kinase C μ by various inhibitors. Inhibition from protein kinase c isoenzymes

et al. 1996

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Various inhibitors were tested for their potential to suppress the kinase activity of protein kinase C tt (PKC~t) in vitro and in vivo. Among the staurosporine-derived, rather selective PKC inhibitors the indolocarbazole G6 6976 previously shown to inhibit preferentially cPKC isotypes proved to be a potent inhibitor of PKC~t with an IC5o of 20 nM, whereas the bisindolylmaleimide G6 6983 was extremely ineffective in suppressing PKCtt kinase activity with a thousand-fold higher ICso of 20 ~M. Other strong inhibitors of PKC~t were the rather unspecific inldbitors staurosporine and K252a. Contrary to the poor inhibition of PKCtt by G~ 6983, this compound was found to suppress in vitro kinase activity of PKC isoenzymes from all three subgroups very effectively with IC5o values from 7 to 60 nM. Thus, Gii 6983 was able to differentiate between PKC~t and other PKC isoenzymes being useful for selective determination of PKC~t kinase activity in the presence of other PKC isoenzymes.

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PH domain: the first anniversary

Cited by 325 publications

References 25 publications

Akt activation by growth factors is a multiple-step process: the role of the PH domain

Akt activation by growth factors is a multiple-step process: the role of the PH domain

A novel partner for the GTP‐bound forms of rho and rac

Inhibition of protein kinase C μ by various inhibitors. Inhibition from protein kinase c isoenzymes

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