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Extracellular Matrix and Adhesion Molecules related Pathways

Chemokine Signaling [ Details | Top ]
Chemokines, or chemotactic cytokines, are a large family of small (6-14 kDa), structurally related proteins that mediate a wide range of biological activities. As a part of normal immune system functions, chemokines are a critical component of basal leukocyte trafficking essential for immune system architecture and development, and immune surveillance. Chemokines also participate in the growth, differentiation, and activation of leukocytes as well as stimulate various effector functions of these cells, such as integrin activation, chemotaxis, superoxide radical production and granule enzyme release. Four classes of chemokines...

Cytokine Network [ Details | Top ]
The immune system recognizes the presence of pathogens by several proteins that bind to molecules secreted by the pathogen or carried on their surface. The cells responsible for these immune responses include the B-Cells, T-Cells, macrophages, neutrophils, basophils, eosinophils, endothelial cells, or mast cells (Ref.1). These cells have distinct roles in the immune system, and communicate with other immune cells by cytokines, which control proliferation, differentiation and function of cells of the immune system. Furthermore, they are involved in processes of inflammation and in the neuronal, haematopoietic and embryonal development of an organism....

Ephrin-EphR Signaling - New [ Details | Top ]
In numerous processes that are vital for the development and maintenance of organism function, cells must communicate crucial information to respond appropriately to the changing environment. As such, RTKs (Receptor Tyrosine Kinases) are transmembrane proteins, which, on receiving an external stimulus, respond by transmitting a signal to the inside of the cell. Of all the RTKs that are found in the human genome, the Eph Receptor family and their ligands the Ephrins, constitutes the largest family....

Epithelial Tight Junctions - New [ Details | Top ]
Epithelia in multicellular organisms constitute the frontier that separates the individual from the environment. Epithelia are sites of exchange as well as barriers, for the transit of ions and molecules from and into the organism. Epithelial cells achieve this by providing cellular borders that cover external and internal surfaces throughout the body. Complexes between adjacent cells include Gap Junctions, Desmosomes, Adherens Junctions (AJs) and Tight Junctions (TJs). Such junctions are quite essential for the modulation of paracellular permeability in various epithelia. Vertebrate epithelial cells exhibit Tight Junction...

ERK Signaling [ Details | Top ]
The MAPK (Mitogen-Activated Protein Kinase) pathway is one of the primordial signaling systems that nature has used in several permutations to accomplish an amazing variety of tasks. It exists in all eukaryotes, and controls such fundamental cellular processes as Proliferation, Differentiation, Survival and Apoptosis. Mammalian MAPK can be divided into four groups based on their structure and function: ERKs (Extracellular signal-Regulated Kinases), p38MAPKs, JNKs (c-Jun NH2-terminal Kinases) and ERK5 (Extracellular signal-Regulated Kinase-5) or BMK. Activation of these MAPKs occurs through a cascade of upstream kinases...

FAK1 Signaling - New [ Details | Top ]
Engagement of integrin receptors with extracellular ligands gives rise to the formation of complex multi-protein structures that link the ECM (Extracellular Matrix) to the cytoplasmic actin cytoskeleton and signaling proteins including Talin, Alpha-actinin, Vinculin, Zyxin, Paxillin and FAK (Focal Adhesion Kinase). These adhesive complexes are dynamic, often heterogeneous structures, varying in size and organization, and signaling through these complexes and focal adhesions have been implicated in the regulation of a number of key cellular processes, including growth factor induced mitogenic signals, cell survival, cell pr...

HGF - New [ Details | Top ]
HGF (Hepatocyte Growth Factor)/SF (Scatter Factor) is a mesenchymal- or stromal-derived multipotent heparan sulfate-binding and dermatan sulfate-binding pleiotropic polypeptide that mediates epithelial-mesenchymal interactions with mitogenic, motogenic and morphogenic activities towards many normal and neoplastic epithelial cells. Initially identified as a potent hepatotrophic factor responsible for vigorous regeneration of the liver, it has now become a well characterized multipotent cytokine with biological functions that reach far beyond the original identifications, operating in virtually every tissue of the body, the...

ILK Signaling - New [ Details | Top ]
The ECM (Extracellular Matrix) provides the structural framework for the formation of tissues and organs. The ECM binds to substrate adhesion molecules on the surface of cells and influences various intracellular signaling pathways that regulate survival, proliferation, polarity and differentiation. The important families of adhesion molecules that bind to the ECM are the Integrins. Integrins consist of Alpha and Beta-subunits and are composed of large extracellular domains and relatively small cytoplasmic domains (Ref.1 & 2). Ligand binding activates signaling cascades that lead to the assembly of a multiprotein complex a...

Inhibition of Angiogenesis by TSP1 - New [ Details | Top ]
Cancer is a multistep process that includes deregulation of cell cycle, transformation, invasion of stroma, angiogenesis and metastasis. Angiogenesis is an essential component for tumor development regulated by both proangiogenic and antiangiogenic factors (Ref.1). It is a multi-step process that includes endothelial cell proliferation, migration, basement membrane degradation, and new lumen organization. Naturally occurring inhibitors of angiogenesis i.e., antiangiogenic factors are found in mammalian tissues, where they help maintain the quiescence of the normal vasculature. Thus, angiogenic inhibitors have been consider...

Integrin Signaling Pathway [ Details | Top ]
Adhesive interactions between cells and ECM (Extracellular Matrix) proteins play a vital role in biological processes, including cell survival, growth, differentiation, migration, inflammatory responses, platelet aggregation, tissue repair and tumor invasion (Ref.4) and perturbing this coordination can lead to events such as malignant transformation. The major groups of proteins mediating these interactions are a family of cell surface receptors known as Integrins, named for their role in integrating the intracellular cytoskeleton with the ECM. The signals from these adhesion receptors are integrated with those originating from growth factor receptors...

JNK Pathway [ Details | Top ]
MAPKs (Mitogen-Activated Protein Kinases) are Serine-threonine protein Kinases that are activated in response to a variety of extracellular stimuli and mediate signal transduction from the cell surface to the nucleus. MAPKs are expressed in multiple cell types including Cardiomyocytes, Vascular Endothelial cells, and Vascular Smooth Muscle Cells. Three major MAPKs include ERKs (Extracellular signal-Regulated Kinases), JNKs (c-Jun NH(2)-terminal protein Kinases), and p38 Kinases. Members of the JNK/SAPK (Stress-Activated Protein Kinase) family of MAPKs are strongly stimulated by numerous Environmental Stresses...

LDL Oxidation in Atherogenesis - New [ Details | Top ]
Atherosclerosis, a chronic inflammatory disease of the arterial wall, is the major cause of morbidity and mortality from CVD (Cardiovascular Disease) in much of the worlds population. The disease involves the formation of Plaques in arterial walls that narrow the arterial passage, restricting blood flow and increasing the risk of occlusion of blood flow by a myocardial infarction. There is now a consensus that Atherosclerosis represents a state of heightened oxidative stress characterized by lipid and protein oxidation in the vascular wall. The Oxidative Modification hypothesis predicts LDL (Low-Density Lipoproteins) oxid...

NF-KappaB Family Pathway [ Details | Top ]
NF-KappaB (Nuclear Factor-KappaB) is a heterodimeric protein composed of different combinations of members of the Rel family of transcription factors. The Rel/ NF-KappaB family of transcription factors are involved mainly in stress-induced, immune, and inflammatory responses. In addition, these molecules play important roles during the development of certain hemopoietic cells, keratinocytes, and lymphoid organ structures. More recently, NF-KappaB family members have been implicated in neoplastic progression and the formation of neuronal synapses. NF-KappaB is also an important regulator...

Notch Signaling [ Details | Top ]
The Notch signaling pathway is a fundamental signaling system used by neighboring cells to communicate with each other in order to assume their proper developmental role. Notch proteins are cell surface transmembrane-spanning receptors which mediate critically important cellular functions through direct cell-cell contact. Interaction between Notch and its proposed ligands initiates a signaling cascade that governs cell fate decisions such as differentiation, proliferation, and apoptosis in numerous tissue types. The core elements of the Notch signaling system include the Notch receptor...

Rac1 Pathway - New [ Details | Top ]
To achieve strong adhesion to their neighbors and sustain stress and tension, epithelial cells develop many different specialized adhesive structures. Breakdown of these structures occurs during tumor progression with the development of a fibroblastic morphology characteristic of metastatic cells. Adhesion receptors of the Cadherin family have been implicated in these cellular processes, which play an important role in the development and maintenance of the differentiated epithelial phenotype during organogenesis and adult life. Cadherin-mediated adhesion requires the activity of the cytosolic proteins of the Rho subfamily...

Ras Pathway [ Details | Top ]
Ras is a membrane-associated guanine nucleotide-binding protein that is normally activated in response to the binding of extracellular signals, such as growth factors, RTKs (Receptor Tyrosine Kinases), TCR (T-Cell Receptors) and PMA (Phorbol-12 Myristate-13 Acetate). Ras signaling affects many cellular functions, which includes cell proliferation, apoptosis, migration, fate specification, and differentiation. Ras acts as a binary signal switch cycling between ON and OFF states, which are characterized in terms of a small molecule, a guanine nucleotide, bound to the protein. In the resting cell, Ras is tightly bound to GDP...

Remodeling of Adherens Junctions - New [ Details | Top ]
The intercellular Adherens Junctions (AJs) are specialized sub-apical structures that function as principle mediators of cell-cell adhesion. Their disassembly correlates with a loss of cell-cell contact and an acquisition of migratory potential. The Adherens Junctions have a crucial role both as sensors of extracellular stimuli and in regulating the dynamics of epithelial cell sheets or with neighboring cells. Cadherins, the Type-I transmembrane proteins of the Adherens Junctions, are principally responsible for homotypic cell-cell adhesion. E-Cadherin, which is present primarily in epithelia, is the best-characterized Cad...

Rho family GTPase - New [ Details | Top ]
The Rho family of small GTP-binding proteins comprises a group of signaling molecules that are activated by a variety of Growth factors, Cytokines, Adhesion molecules, Hormones, Integrins, G-proteins and other biologically active substances and regulate a wide range of biological processes, including Reorganization of the Actin Cytoskeleton, Transcriptional Regulation, Vesicle Trafficking, Morphogenesis, Neutrophil activation, Phagocytosis and activation of the NADPH Oxidase, Mitogenesis, Apoptosis and Tumorigenesis. The mammalian Rho GTPase family currently consists of three subfamilies, Rho (RhoA, RhoB and RhoC), Rac (Ra...

RhoA Pathway - New [ Details | Top ]
Rho is a member of the Ras superfamily of small GTP-binding proteins that play a central role in diverse biological processes such as Actin cytoskeleton organization, Microtubule dynamics, Gene transcription, Oncogenic transformation, Cell cycle progression, Adhesion and Epithelial wound repair. To date, 20 genes encoding different members of the Rho family have been identified in the human genome, and each one acts as a molecular switch to control distinct biochemical pathways. The mammalian Rho GTPase family currently consists of three subfamilies, Rho (RhoA, RhoB and RhoC), Rac (Rac1, Rac2 and Rac3) and CDC42 (Cell Divi...

Signaling in Gap Junction - New [ Details | Top ]
Gap Junction (GJ) channels span two plasma membranes and are formed by the alignment of two hemichannels, each consisting of an oligomer of structural subunit proteins, called Cxs (Connexins). These junctional proteins constitute a multigene family whose members are distinguished according to their predicted molecular weight in kilodaltons. A Connexin structure consists of two extracellular loops (EL), four membrane-spanning domains (TM), one cytoplasmic loop (CL), one N-terminal tail (NT), and one C-terminal tail (CT) (Ref.1 & 2). During intercellular channel formation, six Connexins oligomerize into a Connexon or hemicha...

SMAD Signaling Network [ Details | Top ]
Within the vasculature, TGF-Beta (Transforming Growth Factor-Beta) superfamily of secreted polypeptide growth factors play an important role in a variety of pathophysiologic processes, including angiogenesis, vascular remodeling, atherogenesis and in regulating cellular responses such as growth, proliferation, differentiation, migration, adhesion, survival, and specification of developmental fate. Apart from TGF-Beta, the superfamily also includes the Activins and the BMPs (Bone Morphogenetic Proteins). These factors signal through heteromeric complexes of Type-II and Type-I serine-threonine...

Toll-Like Receptors Pathway [ Details | Top ]
TLRs (Toll-like receptors) are transmembrane proteins expressed by cells of the innate immune system, which recognize invading microbes and activate signaling pathways that launch immune and inflammatory responses to destroy the invaders. Toll receptors were first identified in Drosophila. In mammals, the TLR family includes eleven proteins (TLR1−TLR11). Recently, two new members, TLR12 and TLR13 have been discovered in mouse, but not much information is known about them. Mammalian TLRs consist of an extracellular portion containing Leucine-rich repeats, a Transmembrane region and a Cytoplasmic tail...

Transendothelial Migration of Leukocytes - New [ Details | Top ]
The migratory properties of leukocytes or WBCs (White Blood Cells) are indispensable to drive immune responses throughout the body. Leukocytes fall under two categories according to their morphology that includes Agranulocytes (Lymphocytes and Monocytes) and Granulocytes (Neutrophils, Basophils and Eosinophils). To ensure migration to the proper locations, the trafficking of leukocytes is tightly regulated. The vascular endothelium lining the intima of the blood vessels (both in lymphoid and non-lymphoid tissues) regulates a variety of functions including vascular smooth muscle tone, host-defense reactions, Angiogenesis, a...

VEGF Pathway [ Details | Top ]
The formation of blood vessels occurs either by in situ differentiation of endothelial cell precursors (Angioblasts) and association of these cells to form primitive vessels, a process called Vasculogenesis, or by growth of preexisting vessels, a process called Angiogenesis. Vasculogenesis establishes the primary vascular plexus of the early embryo, whereas development of blood vessels during later embryogenesis and adult life occurs primarily by Angiogenesis. Angiogenesis is an integral feature of capillary sprouts from preexisting blood vessels. It is typically quiescent in the adult, except for pathological situations...

WNT Signaling [ Details | Top ]
The development of tissues and organs in multicellular organisms is controlled by the interplay of several signaling pathways that cross talk to provide positional information and induce cell fate specification. Together with other families of secreted factors such as TGF-Betas (Transforming Growth Factor-Betas), FGFs (Fibroblast Growth Factors), Hedgehog and Notch proteins, WNT (Wingless-Type MMTV Integration Site Family) Growth Factors are crucially implicated in these processes. The WNT genes encode a large family of secreted protein growth factors that have been identified in animals from Hydra to Human...