The LIM and SH3 domain-containing protein, lasp-1, may link the cAMP signaling pathway with dynamic membrane restructuring activities in ion transporting epithelia

Abstract

Lasp-1 is a unique LIM and src homology 3 (SH3) domain-containing protein that was initially identified as a 40 kDa cAMP-dependent phosphoprotein in the HCl-secreting gastric parietal cell. Because cAMP is a potent stimulator of parietal cell acid secretion, we have hypothesized that changes in lasp-1 phosphorylation might be involved in the regulation of ion transport-related activities, perhaps by modulating interactions among cytoskeletal and/or vesicle-associated proteins. In this study, we demonstrate that the cAMP-dependent acid secretory agonist, histamine, induces a rapid, sustained rise in parietal cell lasp-1 phosphorylation and this increase in phosphorylation is closely correlated with the acid secretory response. In addition, elevation of intracellular cAMP concentrations appear to induce a partial redistribution of lasp-1 from the cell cortex, where it predominates along with the gamma-isoform of actin in unstimulated cells, to the beta-actin enriched, apically-directed intracellular canalicular region, which is the site of active proton transport in the parietal cell. Additional studies demonstrate that although lasp-1 mRNA and protein are expressed in a wide range of tissues, the expression is specific for certain actin-rich cell types present within these tissues. For example, gastric chief cells, which contain relatively little F-actin and secrete the enzyme, pepsinogen, by regulated exocytosis, do not appear to express lasp-1. Similarly, lasp-1 was not detected in pancreatic acinar cells, which secrete enzymes by similar mechanisms and also contain relatively low levels of F-actin. Lasp-1 also was not detectable in proximal tubules in the kidney, in gastrointestinal smooth muscle, heart or skeletal muscle. In contrast, expression was prominent in the cortical regions of ion-transporting duct cells in the pancreas and in the salivary parotid gland as well as in certain F-actin-rich cells in the distal tubule/collecting duct. Interestingly, moderate levels of expression were also detected in podocytes present in renal glomeruli and in vascular endothelium. In primary cultures of gastric fibroblasts, lasp-1 was present mainly within the tips of lamellipodia and at the leading edges of membrane ruffles. Taken together these results support the hypothesis that the lasp-1 plays an important role in the regulation of dynamic actin-based, cytoskeletal activities. Agonist-dependent changes in lasp-1 phosphorylation may also serve to regulate actin-associated ion transport activities, not only in the parietal cell but also in certain other F-actin-rich secretory epithelial cell types.

CircTIAM1 overexpression promotes the progression of papillary thyroid cancer by regulating the miR-338-3p/LASP1 axis

“…Increased expression of miR-338-3p suppressed the tumorigenesis of PTC-1 cells in the xenograft mouse model [32]. In addition, miR-338-3p was also reported to suppress cell mobility by downregulating phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2 expression [32]. In the present study, the data indicated that circTIAM1 negatively regulated miR-338-3p activity to modulate cell proliferation and invasive ability.…”

“…For example, miR-338-3p has been identified as a downstream effector of EGFR overexpression in breast cancer [31]. Increased expression of miR-338-3p suppressed the tumorigenesis of PTC-1 cells in the xenograft mouse model [32]. In addition, miR-338-3p was also reported to suppress cell mobility by downregulating phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2 expression [32].…”

“…According to the functional analyses of miR-338-3p targets, LASP1 was negatively regulated by miR-338-3p in PTC cells. LASP1, with a domain of LIM and two-binding domains of actin, interacts with the actin cytoskeleton and transmits signals from the cytoplasm to the nucleus [32,33]. Recently, LASP1 was reported to be highly expressed in different tumor tissues to promote cell proliferation and migration by activation of the PI3K/AKT pathway [34,35].…”

Molecular Analysis of Homocysteic Acid-Induced Neuronal Stress

“…They are (i) vitamin D receptor associated factor 1, also named ERC-55, belonging to the reticulocalbin family, a member of a new subfamily of the EFhand superfamily of Ca 2+ -binding proteins, specifically located in the ER. 34 The protein may contribute to cytoplasmatic signaling pathways potentially inducing apoptosis either indirectly through receptors initiating tyrosine phosphorylation or more directly via the Bcl-2 family system, the ceramide pathway, the death receptors (e.g., Fas) and the stress-activated protein kinase pathways (Jun N terminal kinase and p38); 35 (ii) An expressed sequence with features of a Rho GDP dissociation inhibitor and phosphotyrosine binding SH3 domains; Rho GTPases have been broadly discussed recently as antiinflammatory targets, in particular in neurodegeneration; 36 (iii) The third, Lasp-1, is involved in vesicle trafficking by actin and dynamin binding, has LIM and SH3 domains, 37 again pointing to specific HCA-induced events on the level of tyrosine phosphorylation. 38 The conspicuous occurrence of two members of dihydropyrimidinase-related protein (DHPRP) family prompted a more detailed MS approach: DHPRP, also called the collapsin response mediator protein, is implicated in the developmental process of the nervous system as well as in axonal growth and guidance.…”

A Systematic Compilation of Human SH3 Domains: A Versatile Superfamily in Cellular Signaling

“…SH3DCPs also control the molecular functions of enzymes, receptor activities, and transport processes [ 88 , 89 ]. SH3 domains are protein binding modules in enzymes like phospholipase Cγ [ 90 ].…”