High impact information on Mcf2l

• A crystallographic view of interactions between Dbs and Cdc42: PH domain-assisted guanine nucleotide exchange [1].
• These ideas are exemplified for Dbs, which is strongly implicated in the transformation of NIH 3T3 cells via RhoA and not Cdc42 [2].
• Supporting this conclusion, oncogenic Dbs activates endogenous RhoA but not endogenous Cdc42 in NIH 3T3 cells [2].
• Thus, the PH domain of Dbs (but not Dbl) may be important in modulating association with the plasma membrane, where its GTPase substrates reside [3].
• Suppression of myosin light chain expression by small interfering RNAs impairs Dbs focus formation, thus establishing a direct link between actinomyosin contraction and Rho-specific guanine nucleotide exchange factor transformation [4].

Biological context of Mcf2l

• Dbs transformation is also associated with increased phosphorylation of myosin light chain and stress fiber formation, both of which occur in a ROCK-dependent manner [4].
• The transforming potential of Dbs is substantially activated by the removal of inhibitory sequences that lie outside of the core catalytic sequences, and in this current study we mapped this inhibition to the Sec14 domain [5].
• The transforming cDNA encoded a protein, designated Dbs, which had a region of high sequence similarity to the Dbl proto-oncogene [6].
• A search for transforming genes expressed in brain led to the identification of a novel isoform of Ost, an exchange factor for RhoA and Cdc42 [7].
• The Dbs transgene promoted expansion of double-negative thymocytes in the absence of pre-TCR, but had no effect on pre-TCR-dependent differentiation of double-negative thymocytes into double-positive thymocytes [8].

Anatomical context of Mcf2l

• Co-expression of Dbs with activated Rac1 causes enhanced focus forming activity and elevated levels of GTP.RhoA in NIH 3T3 cells, indicating that Dbs is activated by the interaction [9].
• Dbs was identified in a cDNA-based expression screen for sequences that can cause malignant growth when expressed in murine fibroblasts [4].
• However, translocation of Dbs and the concomitant changes in the actin cytoskeleton were not sufficient to fully activate Dbs transformation [5].
• The Dbs gene was expressed at low levels in several murine hemopoietic cell lines and in thymus and spleen, and at higher levels in other tissues, particularly in brain [6].
• Expression of Ost isoforms potently induced the formation of actin stress fibers and filopodia as well as JNK activity and AP1- and SRF-regulated transcriptional pathways [7].

Associations of Mcf2l with chemical compounds

• Dbs is a Rho-specific guanine nucleotide exchange factor that was identified in a screen for proteins whose expression causes deregulated growth in NIH 3T3 mouse fibroblasts [9].
• In this study, we evaluated the role of phosphoinositide binding to the PH domain in regulating the DH domain function of Dbs in vitro and in vivo [10].
• Surprisingly removal of the NH(2) terminus did not alter the catalytic activity of Dbs in vivo but rather altered its subcellular distribution [5].
• Limited effects of UDCA on Ost-alpha/Ost-beta may jeopardize its therapeutic efficacy [11].
• Absent Ost-alpha/Ost-beta induction in CA-fed FXR(-/-) animals may contribute to increased liver injury in these animals [11].

Physical interactions of Mcf2l

• Crystal structure of the DH/PH fragment of Dbs without bound GTPase [12].

Regulatory relationships of Mcf2l

• Similarly, a competitive inhibitor that blocks RhoA activation also blocks Dbs-mediated transformation [2].
• Multifunctional roles for the PH domain of Dbs in regulating Rho GTPase activation [13].

Other interactions of Mcf2l

• RhoGEF specificity mutants implicate RhoA as a target for Dbs transforming activity [2].
• Critical role of the pleckstrin homology domain in Dbs signaling and growth regulation [10].

Analytical, diagnostic and therapeutic context of Mcf2l

• Comparative sequence analysis suggests that a subset of Dbl-family proteins will utilize their PH domains similarly to Dbs [1].

References