Heterotrimeric G proteins are key players in transmembrane signaling by coupling a huge variety of receptors to channel proteins, enzymes, and other effector molecules. Multiple subforms of G proteins together with receptors, effectors, and various regulatory proteins represent the components of a highly versatile signal transduction system. G protein-mediated signaling is employed by virtually all cells in the mammalian organism and is centrally involved in diverse physiological functions such as perception of sensory information, modulation of synaptic transmission, hormone release and actions, regulation of cell contraction and migration, or cell growth and differentiation. In this review, some of the functions of heterotrimeric G proteins in defined cells and tissues are described.

https://www.physiology.org/doi/pdf/10.1152/physrev.00003.2005

Mammalian G proteins and their cell type specific functions

Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer's disease.

Spermatogenesis is the process by which a single spermatogonium develops into 256 spermatozoa, one of which will fertilize the ovum. Since the 1950s when the stages of the epithelial cycle were first described, reproductive biologists have been in pursuit of one question: How can a spermatogonium traverse the epithelium, while at the same time differentiating into elongate spermatids that remain attached to the Sertoli cell throughout their development? Although it was generally agreed upon that junction restructuring was involved, at that time the types of junctions present in the testis were not even discerned. Today, it is known that tight, anchoring, and gap junctions are found in the testis. The testis also has two unique anchoring junction types, the ectoplasmic specialization and tubulobulbar complex. However, attention has recently shifted on identifying the regulatory molecules that "open" and "close" junctions, because this information will be useful in elucidating the mechanism of germ cell movement. For instance, cytokines have been shown to induce Sertoli cell tight junction disassembly by shutting down the production of tight junction proteins. Other factors such as proteases, protease inhibitors, GTPases, kinases, and phosphatases also come into play. In this review, we focus on this cellular phenomenon, recapping recent developments in the field.

Sertoli-Sertoli and Sertoli-Germ Cell Interactions and Their Significance in Germ Cell Movement in the Seminiferous Epithelium during Spermatogenesis

Dynamin, a 100-kDa GTPase, is an essential component of vesicle formation in receptor-mediated endocytosis, synaptic vesicle recycling, caveolae internalization, and possibly vesicle trafficking in and out of the Golgi. In addition to the GTPase domain, dynamin also contains a pleckstrin homology domain (PH) implicated in membrane binding, a GTPase effector domain (GED) shown to be essential for self-assembly and stimulated GTPase activity, and a C-terminal proline-rich domain (PRD), which contains several SH3-binding sites. Dynamin partners bind to the PRD and may either stimulate dynamin's GTPase activity or target dynamin to the plasma membrane. Purified dynamin readily self-assembles into rings or spirals. This striking structural property supports the hypothesis that dynamin wraps around the necks of budding vesicles where it plays a key role in membrane fission. The focus of this review is on the relationship between the GTPase and self-assembly properties of dynamin and its cellular function.

Dynamin and its Role in Membrane Fission

The primary functions of the gastrointestinal tract have traditionally been perceived to be limited to the digestion and absorption of nutrients and to electrolytes and water homeostasis. A more at...

Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer

Gastrin-releasing peptide and cancer.

Gastrins, cholecystokinins and gastrointestinal cancer

Adhesion between neighbouring epithelial cells is a crucial and tightly controlled process. In the gastrointestinal tract, the integrity of cell-cell contacts is essential for the regulation of electrolyte absorption and for the prevention of tumour metastasis. We recently showed that migration of the gastric epithelial cell line IMGE-5 is stimulated by the nonamidated form of the hormone gastrin(17). Here, we examine the effect on cell-cell adhesion of the prohormone progastrin, the concentration of which is increased in the plasma of patients with colorectal carcinoma. Progastrin induced the dissociation of both tight junction (TJ) and adherens junction (AJ) complexes in IMGE-5 cells. In progastrin-secreting DLD-1 human colorectal carcinoma cells, expression of an antisense gastrin construct restored membrane localisation of zonula occludens-1 (ZO-1), occludin, beta-catenin and E-cadherin. This restoration was reversed by treatment with exogenous progastrin. Endogenous or exogenous progastrin also increased the paracellular flux of mannitol, and induced cell migration of several gastrointestinal cell lines. In addition, progastrin enhanced Src tyrosine kinase activity and induced a spatial delocalisation of protein kinase C alpha. Using dominant-negative mutants and pharmacological inhibitors, we showed that the stimulation of Src kinase activity was essential for the regulation of TJs. By contrast, the dissociation of AJs involved phosphatidylinositol 3-kinase, partly through the formation of a complex with protein kinase C alpha. We conclude that separate pathways mediate the disruption of AJs and TJs by progastrin. Either pathway may contribute to the co-carcinogenic role of this prohormone in colorectal carcinoma.

/pdf/adherens-junctions-and-tight-junctions-are-regulated-via-5pxygil0n0.pdf

Adherens junctions and tight junctions are regulated via different pathways by progastrin in epithelial cells

P21-activated kinase 1 stimulates colon cancer cell growth and migration/invasion via ERK- and AKT-dependent pathways

The hormone gastrin stimulates acid secretion by gastric parietal cells and acts as a growth factor for the gastric mucosa. Gastrin receptors with dissociation constants of approximately 0.5 nM have been detected on isolated gastric parietal cells, and on some cell lines derived from colon carcinomas. We now report that gastrin is also bound by five cell lines derived from human gastric carcinomas, but that the affinities of these lines for gastrin range from 0.2 to 1.3 microM. Cholecystokinin8 binds to the cell line Okajima with an affinity similar to gastrin17, while shorter gastrin analogues bind with reduced affinity. Binding of gastrin is unaffected by acetylcholine, histamine, or a number of other hormones with the exception of insulin which inhibits binding with an IC50 value of 0.5 microM. The ability to bind gastrin with affinities in the microM range appears to be a property widespread among other tumor cell lines.

/pdf/binding-of-gastrin17-to-human-gastric-carcinoma-cell-lines-29dea5tqto.pdf

Graham S. Baldwin

Papers

Gastrin-releasing peptide and cancer.

Gastrins, cholecystokinins and gastrointestinal cancer

Adherens junctions and tight junctions are regulated via different pathways by progastrin in epithelial cells

P21-activated kinase 1 stimulates colon cancer cell growth and migration/invasion via ERK- and AKT-dependent pathways

Binding of Gastrin17 to Human Gastric Carcinoma Cell Lines