Direct interaction of insulin-like growth factor-1 receptor with leukemia-associated RhoGEF

Abstract

Insulin-like growth factor (IGF)-1 plays crucial roles in growth control and rearrangements of the cytoskeleton. IGF-1 binds to the IGF-1 receptor and thereby induces the autophosphorylation of this receptor at its tyrosine residues. The phosphorylation of the IGF-1 receptor is thought to initiate a cascade of events. Although various signaling molecules have been identified, they appear to interact with the tyrosine-phosphorylated IGF-1 receptor. Here, we identified leukemia-associated Rho guanine nucleotide exchange factor (GEF) (LARG), which contains the PSD-95/Dlg/ZO-1 (PDZ), regulator of G protein signaling (RGS), Dbl homology, and pleckstrin homology domains, as a nonphosphorylated IGF-1 receptor-interacting molecule. LARG formed a complex with the IGF-1 receptor in vivo, and the PDZ domain of LARG interacted directly with the COOH-terminal domain of IGF-1 receptor in vitro. LARG had an exchange activity for Rho in vitro and induced the formation of stress fibers in NIH 3T3 fibroblasts. When MDCKII epithelial cells were treated with IGF-1, Rho and its effector Rho-associated kinase (Rho-kinase) were activated and actin stress fibers were enhanced. Furthermore, the IGF-1–induced Rho-kinase activation and the enhancement of stress fibers were inhibited by ectopic expression of the PDZ and RGS domains of LARG. Taken together, these results indicate that IGF-1 activates the Rho/Rho-kinase pathway via a LARG/IGF-1 receptor complex and thereby regulates cytoskeletal rearrangements.

Elevated serum insulin-like growth factor binding protein-2 is associated with a high relapse risk after hematopoietic stem cell transplantation in childhood AML

“…An interaction with the IGF-I-receptor is also possible. 37 Furthermore, the different conditioning regimens and the occurrence of graftversus-host disease had no influence on changes in serum IGFs and IGFBPs in our patients. These findings are supported by the results of Munker et al 38 They found no direct correlation between both the IGF-system and the severity of graft-versus-host disease as well as levels of interleukin-6 and the time to hematopoietic recovery.…”

The semaphorin receptor plexin-B1 signals through a direct interaction with the Rho-specific nucleotide exchange factor, LARG

“…Both have been implicated in signal transduction of trimeric G protein-coupled receptor signaling (23,(32)(33)(34). LARG has also been shown to directly interact with the insulin-like growth factor (IGF) receptor (26). The PDZ domain of LARG interacts with the C-terminal residues of the IGF receptor.…”

“…LARG contains a type I PDZ domain and is predicted to interact with the PDZ binding site consensus sequence X-S͞T-X-located at the extreme C terminus of the target protein (26). Inspection of the plexin-B1 C terminus revealed the residues VTDL, which conforms to such a PDZ binding site (Fig.…”

Homo- and hetero-oligomerization of PDZ-RhoGEF, LARG and p115RhoGEF by their C-terminal region regulates their in vivo Rho GEF activity and transforming potential

“…Foci of transformation were counted in triplicate plates in independent transfections, and the number of foci per g of transfected DNA for each construct is documented in (Fukuhara et al, 2001). These RhoGEFs can be further regulated by tyrosine phosphorylation , and two of these GEFs, PRG and LARG, can be activated through the association of their PDZ domains with insulin-like growth factor receptor or the cytoplasmic tail of Plexin B (Taya et al, 2001;Aurandt et al, 2002;Perrot et al, 2002;Swiercz et al, 2002). During the course of characterizing a PRG-specific antiserum, we discovered that this GEF can form oligomers through its C-terminal region.…”

“…For example, recently reported evidence indicates that two of these RGL-containing RhoGEFs, PRG and LARG, can be phosphorylated in tyrosine residues by FAK in response to agonist stimulating G proteins , and that these RhoGEFs can associate through their PDZ domain to insulin-like growth factor receptors (Taya et al, 2001) and Plexin B (Aurandt et al, 2002;Perrot et al, 2002;Swiercz et al, 2002), the latter a semaphorin receptor which controls axon guidance during development. Additionally, G 12/13 binding to the RGL domain of p115RhoGEF was shown to partially activate its GEF activity towards Rho, suggesting that the Nterminus of p115RhoGEF may impose an autoinhibition on the DH/PH module .…”