Hematopoietic progenitor kinase 1 (HPK1) negatively regulates prostaglandin E2–induced fos gene transcription

Prostaglandin E2 (PGE2) is the predominant eicosanoid product released by macrophages at the site of inflammation. Binding of PGE2 to its cognate 7 transmembrane-spanning G protein–coupled receptors (GPCRs) activates signaling pathways, leading to the synthesis of the Fos transcription factor. Because the Ste20 serine/threonine protein kinase (S/TPK) is a critical signal transducer for the G protein–coupled pheromone receptor in Saccharomyces cerevisiae, we postulated that the PGE2 GPCRs may activate one of the Ste20 mammalian orthologs. We demonstrate here that the catalytic activity of a hematopoietic cell–restricted, Ste20-related S/TPK, HPK1, is positively regulated by exposure to physiological concentrations of PGE2. Furthermore, ectopic expression studies implicated HPK1 as a negative regulator of PGE2-induced transcription of the fos gene. Our data suggest that PGE2-induced activation of HPK1 may represent a novel negative regulatory pathway capable of modulating PGE2-mediated gene transcription.

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G-protein-coupled receptors in aldosterone-producing adenomas: a potential cause of hyperaldosteronism

Journal of Endocrinology ◽

10.1677/joe-07-0037 ◽

2007 ◽

Vol 195 (1) ◽

pp. 39-48 ◽

Cited By ~ 65

Author(s):

Ping Ye ◽

Barbara Mariniello ◽

Franco Mantero ◽

Hirotaka Shibata ◽

William E Rainey

Keyword(s):

G Protein ◽

Serotonin Receptor ◽

Ectopic Expression ◽

Fold Increase ◽

G Protein Coupled Receptors ◽

Genomic Expression ◽

Expression Arrays ◽

Aldosterone Production ◽

Aldosterone Producing Adenoma ◽

G Protein Coupled

The source of aldosterone in 30–40% of patients with primary hyperaldosteronism (PA) is unilateral aldosterone-producing adenoma (APA). The mechanisms causing elevated aldosterone production in APA are unknown. Herein, we examined the expression of G-protein-coupled receptors (GPCRs) in APA and demonstrated that when compared with normal adrenals, there is a general elevation of certain GPCR in many APA and/or ectopic expression of GPCR in others. RNA samples from normal adrenals (n = 5), APAs (n = 10), and cortisol-producing adenomas (CPAs; n = 13) were used on 15 genomic expression arrays, each of which included 223 GPCR transcripts presented in at least 1 out of 15 of the independent microarrays. The array results were confirmed using real-time RT-PCR (qPCR). Four GPCR transcripts exhibited a statistically significant increase that was greater than threefold when compared with normal adrenals, suggesting a general increase in expression when compared with normal adrenal glands. Four GPCR transcripts exhibited a > 15-fold increase of expression in one or more of the APA samples when compared with normal adrenals. qPCR analysis confirmed array data and found the receptors with the highest fold increase in APA expression to be LH receptor, serotonin receptor 4, GnRH receptor, glutamate receptor metabotropic 3, endothelin receptor type B-like protein, and ACTH receptor. There are also sporadic increased expressions of these genes in the CPAs. Together, these findings suggest a potential role of altered GPCR expression in many cases of PA and provide candidate GPCR for further study.

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SCAR, a WASP-related Protein, Isolated as a Suppressor of Receptor Defects in Late Dictyostelium Development

The Journal of Cell Biology ◽

10.1083/jcb.142.5.1325 ◽

1998 ◽

Vol 142 (5) ◽

pp. 1325-1335 ◽

Cited By ~ 185

Author(s):

James E. Bear ◽

John F. Rawls ◽

Charles L. Saxe

Keyword(s):

Actin Cytoskeleton ◽

G Protein ◽

Receptor Gene ◽

Cell Types ◽

G Protein Coupled Receptors ◽

Negative Regulator ◽

Small Cells ◽

Gene Encoding ◽

Tip Formation ◽

G Protein Coupled

G protein–coupled receptors trigger the reorganization of the actin cytoskeleton in many cell types, but the steps in this signal transduction cascade are poorly understood. During Dictyostelium development, extracellular cAMP functions as a chemoattractant and morphogenetic signal that is transduced via a family of G protein–coupled receptors, the cARs. In a strain where the cAR2 receptor gene is disrupted by homologous recombination, the developmental program arrests before tip formation. In a genetic screen for suppressors of this phenotype, a gene encoding a protein related to the Wiskott-Aldrich Syndrome protein was discovered. Loss of this protein, which we call SCAR (suppressor of cAR), restores tip formation and most later development to cAR2− strains, and causes a multiple-tip phenotype in a cAR2+ strain as well as leading to the production of extremely small cells in suspension culture. SCAR−cells have reduced levels of F-actin staining during vegetative growth, and abnormal cell morphology and actin distribution during chemotaxis. Uncharacterized homologues of SCAR have also been identified in humans, mouse, Caenorhabditis elegans, and Drosophila. These data suggest that SCAR may be a conserved negative regulator of G protein-coupled signaling, and that it plays an important role in regulating the actin cytoskeleton.

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