Leukocyte-specific protein 1 targets the ERK/MAP kinase scaffold protein KSR and MEK1 and ERK2 to the actin cytoskeleton

Abstract

The identification and characterization of scaffold and targeting proteins of the ERK/MAP kinase pathway is important to understand the function and intracellular organization of this pathway. The F-actin binding protein leukocyte-specific protein 1 (LSP1) binds to PKCβI and expression of B-LSP1, an LSP1 truncate containing the PKCβI binding residues, inhibits anti-IgM-induced translocation of PKCβI to the plasma membrane and anti-IgM-induced activation of ERK2. To understand the role of LSP1 in the regulation of PKCβI-dependent ERK2 activation, we investigated whether LSP1 interacts with ERK/MAP kinase pathway components and targets these proteins to the actin cytoskeleton. We show that LSP1 associates with the ERK scaffold protein KSR and with MEK1 and ERK2. LSP1-associated MEK1 is activated by anti-IgM treatment and this activation is inhibited by expression of B-LSP1, suggesting that the activation of LSP1-associated MEK1 is PKCβI dependent. Confocal microscopy showed that LSP1 targets KSR, MEK1 and ERK2 to peripheral actin filaments. Thus our data show that LSP1 is a cytoskeletal targeting protein for the ERK/MAP kinase pathway and support a model in which MEK1 and ERK2 are organized in a cytoskeletal signaling complex together with KSR, PKCβI and LSP1 and are activated by anti-IgM in a PKCβI-dependent manner.

Discovering biomarkers from gene expression data for predicting cancer subgroups using neural networks and relational fuzzy clustering

“…The gene LSP1 is involved in transendothelial migration of neutrophil and actin cytoskeleton organization through MEK1 and ERK2 pathways [22,23]. We observed downregulation of LSP1 in EWS, NHL and NB but reasonably higher expression in the RMS group of tumors.…”

The ERK Cascade: Distinct Functions within Various Subcellular Organelles

“…170,171 Another ERK1/2 scaffold protein that is also an actin-binding protein is LSP1, which associates with MEK1, ERK2, and KSR and targets them to peripheral actin filaments and thereby regulates signals to proliferation. 172,173 Finally, not only are ERK1/2 regulated by cytoskeletal elements, they can also regulate cytoskeletal reorganization and M Monographs thereby downstream cellular processes. An example of such an effect is the influence of ERK1/2 on cell motility, which is mediated in part by phosphorylation of myosin light chain kinase (MLCK) to enhance its activity and facilitate cell motility.…”

Gene Repression by Pax5 in B Cells Is Essential for Blood Cell Homeostasis and Is Reversed in Plasma Cells

“…Pax5-repressed genes also code for the transmembrane protein CD47 (Brown and Frazier, 2001) and tetraspanin Tm4sf2 (Zemni et al, 2000), which regulate adhesiondependent signaling by interacting with integrin receptors, while Embigin (Emb) promotes cell adhesion in a yet unknown manner (Huang et al, 1993). In addition to the chemokine receptors CCR2 and CCR5, other Pax5-repressed regulators of cell migration and adhesion include the signal-transducing molecule Lsp1 (Harrison et al, 2004), the Rho guanine nucleotide exchange factor Vav3 (Gakidis et al, 2004), and the Rho GTPaseactivating protein Daam1 (Habas et al, 2001), which are involved in controlling the actin cytoskeleton. In summary, Pax5 alters the adhesion and migration properties of lymphoid progenitors by downregulating multiple components of chemokine and intergrin signaling pathways.…”