Distinct roles for DH and PH domains in the Lbc oncogene

Olson, Michael F.; Sterpetti, Paola; Nagata, Koh‐ichi; Toksoz, Deniz; Hall, Alan

doi:10.1038/sj.onc.1201594

Cited by 66 publications

(50 citation statements)

References 20 publications

(27 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The DH domain is involved in the nucleotide exchange activity and the PH domain determines its membrane association. Both domains are required for the transforming activity (11,46,47). To define the function of p115-RhoGEF involved in the inhibition, a number of p115 deletion mutants were tested.…”

Section: Activation Of P115-rhogef Suppresses Hiv-1 Replicationmentioning

confidence: 99%

Modulation of HIV-1 Replication by a Novel RhoA Effector Activity

Wang

Zhang

Solski

et al. 2000

The Journal of Immunology

View full text Add to dashboard Cite

The RhoA GTPase is involved in regulating actin cytoskeletal organization, gene expression, cell proliferation, and survival. We report here that p115-RhoGEF, a specific guanine nucleotide exchange factor (GEF) and activator of RhoA, modulates HIV-1 replication. Ectopic expression of p115-RhoGEF or Gα13, which activates p115-RhoGEF activity, leads to inhibition of HIV-1 replication. RhoA activation is required and the inhibition affects HIV-1 gene expression. The RhoA effector activity in inhibiting HIV-1 replication is genetically separable from its activities in transformation of NIH3T3 cells, activation of serum response factor, and actin stress fiber formation. These findings reveal that the RhoA signal transduction pathway regulates HIV-1 replication and suggest that RhoA inhibits HIV-1 replication via a novel effector activity.

show abstract

Section: Activation Of P115-rhogef Suppresses Hiv-1 Replicationmentioning

confidence: 99%

Modulation of HIV-1 Replication by a Novel RhoA Effector Activity

Wang

Zhang

Solski

et al. 2000

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Detailed structural, biochemical, and biological analyses have verified the critical role of the PH domain in DH domain function, although the specific role and involvement can vary significantly among different Dbl family proteins. When evaluated, the PH domain has been found to be indispensable for DH domain function (12)(13)(14)(15)(16)(17)(18). One exception is Tiam1, where the DH domain-associated PH domain was found to be dispensable for function, and instead, a second PH domain was found to be essential for membrane association and activity (19).…”

mentioning

confidence: 99%

Requirement For C-terminal Sequences in Regulation of Ect2 Guanine Nucleotide Exchange Specificity and Transformation

Solski

Wilder

Rossman

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Ect2 was identified originally as a transforming protein and a member of the Dbl family of Rho guanine nucleotide exchange factors (GEFs). Like all Dbl family proteins, Ect2 contains a tandem Dbl homology (DH) and pleckstrin homology (PH) domain structure. Previous studies demonstrated that N-terminal deletion of sequences upstream of the DH domain created a constitutively activated, transforming variant of Ect2 (designated ⌬N-Ect2 DH/PH/C), indicating that the N terminus served as a negative regulator of DH domain function in vivo. The role of sequences C-terminal to the DH domain has not been established. Therefore, we assessed the consequences of mutation of C-terminal sequences on Ect2-transforming activity. Surprisingly, in contrast to observations with other Dbl family proteins, we found that mutation of the invariant tryptophan residue in the PH domain did not impair ⌬N-Ect2 DH/PH/C transforming activity. Furthermore, although the sequences Cterminal to the PH domain lack any known functional domains or motifs, deletion of these sequences (⌬N-Ect2 DH/PH) resulted in a dramatic reduction in transforming activity. Whereas ⌬N-Ect2 caused formation of lamellipodia, ⌬N-Ect2 DH/PH enhanced actin stress fiber formation, suggesting that C-terminal sequences influenced Ect2 Rho GTPase specificity. Consistent with this possibility, we determined that ⌬N-Ect2 DH/PH activated RhoA, but not Rac1 or Cdc42, whereas ⌬N-Ect2 DH/PH/C activated all three Rho GTPases in vivo. Taken together, these observations suggest that regions of Ect2 C-terminal to the DH domain alter the profile of Rho GTPases activated in vivo and consequently may contribute to the enhanced transforming activity of ⌬N-Ect2 DH/PH/C.

show abstract

“…For Rho GTPases, the exchange of bound GDP for GTP is catalyzed by a large class of guanine nucleotide exchange factors (GEFs) 1 related to the gene product for Dbl (diffuse B-cell lymphoma) (10). Similarly to constitutively active forms of Rho GTPases, the unregulated activation of Dbl family members is generally associated with cellular transformation, and many Dbl family members are proto-oncogenic (7,11).…”

mentioning

confidence: 99%

Quantitative Analysis of the Effect of Phosphoinositide Interactions on the Function of Dbl Family Proteins

Snyder¹,

Rossman²,

Baumeister³

et al. 2001

Journal of Biological Chemistry

View full text Add to dashboard Cite

Rho GTPases cycle between inactive and active states based upon conformational alterations imposed by the state of bound guanine nucleotide. Rho GTPases bound to GDP are inactive in downstream signaling, while GTP-bound versions modulate a plethora of downstream effectors typically associated with morphological alterations of the cytoskeleton and activation of stress response genes (1-5). Consistent with their central role in regulating cellular differentiation and proliferation, constitutively active Rho GTPases are sufficient to promote cellular transformation. Similarly, Ras-induced transformation is dependent on Rac1, a Rho GTPase (6 -9). Since the proper control of a multitude of signaling cascades by G proteins depends critically upon the state of bound nucleotide, G proteins have evolved several, tightly controlled processes for regulating the binding and hydrolysis of guanine nucleotides. For Rho GTPases, the exchange of bound GDP for GTP is catalyzed by a large class of guanine nucleotide exchange factors (GEFs) 1 related to the gene product for Dbl (diffuse B-cell lymphoma) (10). Similarly to constitutively active forms of Rho GTPases, the unregulated activation of Dbl family members is generally associated with cellular transformation, and many Dbl family members are proto-oncogenic (7, 11).Dbl family proteins invariantly contain an ϳ300-amino acid span composed of a Dbl homology (DH) domain in tandem with a pleckstrin homology (PH) domain (12, 13). DH domains are sufficient to catalyze nucleotide exchange; however, exchange activity is often enhanced by inclusion of the adjacent PH domain (14). While DH domains serve as the major docking site for Rho GTPases, roles for the adjacent, conserved PH domains remain unclear. The invariant DH/PH domain architecture in all Dbl family members strongly suggests that associated PH domains have a unique and highly conserved role in regulating nucleotide exchange. Simple structural stabilization of the DH domain by the adjacent PH domain as suggested by the Tiam1-DH/PH⅐Rac1 crystal structure (15) is an unsatisfactory explanation for the universal pairing of DH and PH domains. A multitude of other domains could easily be imagined to serve this purpose.In many other proteins, PH domains bind phosphoinositides to function as regulated tethers to cellular membranes (16 -20). Although PH domains typically share very low sequence identity, all possess a common ␤-sandwich fold capped at one end with a C-terminal helix. Numerous studies indicate that PH domains generally bind phosphoinositides with a wide degree of affinity and specificity via clusters of basic residues located within the highly variable loops between strands ␤ 1 /␤ 2 and ␤ 3 /␤ 4 (21-23). Several reports present conflicting data describ-* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.¶ Supported by an NIH Molecular and Cellul...

show abstract

Distinct roles for DH and PH domains in the Lbc oncogene

Cited by 66 publications

References 20 publications

Modulation of HIV-1 Replication by a Novel RhoA Effector Activity

Modulation of HIV-1 Replication by a Novel RhoA Effector Activity

Requirement For C-terminal Sequences in Regulation of Ect2 Guanine Nucleotide Exchange Specificity and Transformation

Quantitative Analysis of the Effect of Phosphoinositide Interactions on the Function of Dbl Family Proteins

Contact Info

Product

Resources

About