Cell Signalling [1 ed.] 9789350432303, 9789350243183

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CELL SIGNALLING

C.B.Powar M.Sc., PIt.D.

ChiefEditor, Bioscientia, Professor Emeritus, Biotechnology, Hislop School of Biotechnology, Nagpur, Former Principal, Sindhu Mahavidyalaya, NAGPUR.

K~}I

GfIimalaya GFublishing GRouse MUMBAI • DELHI •

NAGPUR

•

BANGALORE • HYDERABAD

© Author

ISBN : 978-93-5024-318-3 FIRST EDITION :2010

Published by

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PREFACE The existence of the plasma membrane was postulated long before it was actually seen, because it was too thin to be resolved by light microscopy. It was only in the early 1950s that the membrane was seen under the electron microscope. For long the principal function of the plasma membrane, which is found surrounding all cells, was thought to be retention of the cell contents. Later, it as thought to function primarily in the regulation of tr~nsport of molecules into and out of the cell, and in conduction of nerve impulses in specialized cells such as nerve cells. It was only in the last quarter of the 20th century that the role of the plasma membrane in communication between cells began to be elucidated, and the membrane now has the status of a cell organelle. Cells do not live in isolation, but communicate with each other. They continually receive information from their surroundings, and respond in ways that are determined by their genes, as well as epigenetic factors (chemical and physical agents) that alter the ways in which genes are expressed. Signal transduction pathways are evolutionarily ancient, and are found in the prokaryotes. Unicellular eukaryotes such as yeasts, moulds and protozoans coordinate aggregation of cells for mating and differentiation by pheromones, molecules that are secreted outside the cell. Even more important is the signalling within the organism found in the multicellular plants and animals. Metabolic processes within the cell, growth and differentiation of tissues, synthesis and secretion of proteins and compartmt-------r--KKJ;;IN:0A~S~E:---I---~('-_ _ INTEGRIN BINDING

C

FOCAL ADHESION BINDING

Fig. 8.9. Domains of some nonreceptor tyrosine kinases (NRTKs).

Enzyme-linked cell surface receptors

palmitoylation. NRTKs possess a tyrosine kinase domain and also domains mediating protein-protein, protein-lipid and protein-DNA interactions. NRTKs are critical components of immune system regulation. The Src family of NRTKs take part in a variety of signalling processes, including mitogenesis, T-cell and B-cell activation and restructuring of the cytoskeleton. Substrates for Src include PDGFR, EGFR, Fak (focal adhesion kinase), the adaptor protein p130Cas (involved in integrin-mediated and growth factor-mediated signalling) and contactin (actin binding protein). Several human sarcomas, including breast, lung and colon cancers, are associated with Src. The Jak family NRTKs are associated with cytoplasmic receptors, which they phosphorylate on activation.

18. RECEPTOR GUANYLYL CYCLASES (RGCs)1 Guanylyl cyclase is the enzyme responsible for the catalytic conversion of GTP to 3'5' -cyclic guanosine monophosphate or cyclic GMP (cGMP). There is considerable homology between the catalytic domains of various gua'nylyl cyclases and the catalytic domains of mammalial adenylyl cyclase. However, adenylyl cyclase is found only in the membrane-bound (particulate) fractions, whereas guanylyl cyclase is found both in membrane bound and cytosolic fractions. 1. MEMBRANE GUANYLYL CYCLASES (Fig.B.10A) The membrane guanylyl cyclases include three natriuretic peptide receptors, the ANP-C, GC-A and GC-B receptors, and the guanylin and bacterial heat-stable enterotoxin receptor GC-C. In the early 1980s a peptide obtained from the heart (atrial natriuretic peptide, ANP) was found to stimulate natriuresis, diuresis and vasodilation. It was found to elevate cGMP levels in intact cells. Subsequently, membrane guanylyl cyclases serving as cell surface receptors were found for ANP and a variety of extracellular peptide ligands. These receptors have an extracellular domain that functions in natriuretic-peptide or other peptide binding, a transmembrane domain and an intracellular or cytosolic domain. (0 ANP C receptor. This receptor is the ANP clearance receptor, so called because it clears ANP from the circulation. It is a homodimer of a 65 kDa protein. Each polypeptide consists of an extracellular domain which functions in natriuretic peptide-binding

III

Cell signalling

112

A.MEMBRANEGUANYLYLCYCLASES TRANSMEMBRANE DOMAIN

EXTRACELLULAR DOMAIN

I

/

37amino acids

N - - 4 H I t - - - -.....--4~-----..,f-~ C Atrial natriuretic peptide (ANP)-binding domain

INTRACELLULAR DOMAIN

ANP-C (ANP clearance) receptor Clears excess ANP from circulation Homodimer of a 65-kDa protein No guanylyl cyclase activity. C

ANP-binding domain

N

GC-A (guanylyl cyclase-A) receptor Guanylyl cyclase activity in guanylyl cyclase catalytic domain Monomeric 130 kDa protein

~*-----------~-----~~~~==~ ANP-binding domain

C

GC-B (guanylyl cyclase-B) receptor Same as GC-A C

. Guanylin and bacterial heat-stable endotoxin-binding domain

GC-C (guanylylcyclase-C) receptor Protein kinase Guanylyl cyclase like domain catalytic domain

B. SOLUBLE (CYTOSOLlC) GUANYLYL CYCLASE Nitric oxide (NO)-activated A guanylyl cyclase related to the 13-subunit is also known

~~r~U:~;;1

-..I.-:-'--I{~~~~~~_~~~~ a.-subunit I I (77 kDa) Regulatory domains

Guanylyl cyclase domains

Fig. 8.10. Domain structure of the guanylyl cyclase family members .

• _Ligand (atrial natriuretic peptide, ANP) Exterior Plasma Cytosol Receptor

Guanylyl cyclase ~ activity GTP 3'-5'-cGMP+PPi

Fig. 8.11. Binding of ligand (atrial natriuretic peptide, ANP) to its receptor activates the receptor and stimulates its guanylyl cyclase activity, leading to synthesis of cGMP from GTP.

Enzyme-linked cell surface receptors

and has five cysteine residues, a transmembrane domain and a very . short cytosolic domain of 37 amino acids. Because of the absence of a guanylyl cyclase catalytic domain, the ANP-C receptor has no guanylyl cyclase activity. (ii) GC-A receptor. The guanylyl cyclase-A receptor has an intracellular cytosolic region that contains a protein kinase-like domain, and a guanylyl cyclase 'catalytic domain towards the carboxyl tenninus. The extracellular domain shows substantial sequence similarity to the ANP-C receptor, but has six cysteine residues. GC-A, like GC-B and GC-C, functions as a monomeric 130 kDa protein. The atrial natriuretic peptide (ANP) , also called the atrial natriuretic factor (AN F) , is a small peptide hormone that is released in the atrium of the heart in response to high blood pressure. ANP is carried through the blood stream to the kidneys. Here it acts as a ligand and binds to a guanylyl cyclase receptor in the collecting duct, sti~ulating the guanylyl cyclase activity of .the guanylyl cyclase catalytic domain (Fig.8.11). This leads to the synthesis of cGMP from GTP (GTP--73'-5'-cGMP), resulting in elevation of cGMP concentration in the cell. This in turn leads to increased renal excretion of Na+ ions, and consequently, loss of water. Loss of water from the blood vascular system reduces the blood volume. As a result, the initial stimulus that led to the secretion of ANP is removed, and blood pressure is lowered. The smooth muscle in the wall of blood vessels also has ANP receptors coupled to guanylyl cyclase. ANP on binding to its receptor causes vasodilation or relaxation of blood vessels, leading to reduction in blood pressure. (iii) GC-B receptor. The guanylyl cyclase-B receptor is

structurally and functionally similar to the GC-A receptor. (iv) GC-C receptor. The guanylyl cyclase-C receptor does not show much similarity with the GC-A and GC-B receptors in its extracellular domain, although its cytosolic domain is similar. The GC-C receptor is a receptor-guanylyl cyclase found in the plasma membrane of intestinal epithelial cells. It is activated by the intestinal peptide guanylin, which regulates Cl- secretion in the intestine. The receptor is also the target of a bacterial heat-stable endotoxin that triggers severe diarrhoea .

113

Cell signalling

114

00 • •• •

E

C Type I receptor (T~R-I) TGF-~ (ligand)

Kinase

complex -B (ligand)

KinaseTl'R-1i homodimer

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