Signaling Pathways

• Notch
  • Notch-1
  • Aph1a
  • Patched
  • Decorin
• TGF Family
  • Lefty
  • Smad2
  • Thrombospondin
  • Phospho T8 (Smad2 )
  • WNT
  • GSK3
  • LR5
• Throphoblast
  • CDX2
  • SOX9
  • TBR/Eomes

• Notch-1
  The Notch gene belongs to a family of epidermal growth factor (EGF) like homeotic genes, which encode transmembrane proteins with a variable number of cysteine rich EGF like repeats in the extracellular region. Four notch genes have been described in mammals: Notch1, Notch2, Notch3 and Notch4(Int3), which have been implicated in the differentiation of the nervous system and other structures. The EGF like proteins Delta and Serrate have been identified as ligands of Notch1. Mature Notch proteins are heterodimeric receptors derived from the cleavage of Notch pre-proteins into an extracellular subunit (NEC) containing multiple EGF like repeats and a transmembrane subunit including intracellular region (Ntm).
  
  The Notch signaling pathway was first identified in Drosophila. The Notch 1 protein is a single pass transmembrane receptor activated through the Delta (Dl) and Serrate (Ser) ligands in Drosophila (and their mammalian counterparts Delta like 3 and Jagged 1 and 2). Activation results in the proteolytic cleavage of the cytoplasmic portion of Notch (120kDa) which localizes to the nucleus to interact with DNA binding proteins (RB Jk/KBF2/CBF1). The interaction of Notch with these proteins converts them from transcriptional repressors to activators, thus affecting the expression of a variety of target genes.
  
  During maturation, the Notch molecule is cleaved by furin like convertase at the extracellular domain. Upon binding to a ligand such as Delta1, or upon extracellular calcium depletion, the C terminal Notch 1 fragment dissociates from its N terminal counterpart and is further cleaved between Gly1743 and Val1744. The resulting activated cytosolic fragment translocates to the nucleus and activates Notch related transcription.
  
  
• Aph1a
  Anterior Pharynx Defective 1 (APH1a) is an integral transmembrane protein forming a component of the gamma-secretase complex, a complex composed of a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PEN2. The gamma-secretase complex is an endoprotease complex that catalyzes the intramembrane cleavage of integral proteins such as Notch receptors and APP (beta-amyloid precursor protein).
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  SHH
  Gil1
  Gil2
  
  
• Patched
  PTCH (Patched protein homolog 1) is a receptor for sonic hedgehog (SHH), indian hedgehog (IHH) and desert hedgehog (DHH). PTCH associates with the smoothened protein (SMO) to transduce the hedgehog's proteins signal.PTCH has a tumor suppressor function, as inactivation of this protein is probably a necessary, if not sufficient step for tumorigenesis. PTCH is expressed in the adult brain, lung, liver, heart, placenta, skeletal muscle, pancreas and kidney. It is also expressed in tumor cells but not in normal skin. During development PTCH is found in all major target tissues of sonic hedgehog, such as the ventral neural tube, somites, and tissues surrounding the zone of polarizing activity of the limb bud.
  
  
• Sonic Hedgehog

• Decorin
  Decorin is a member of the small, leucine rich proteoglycan (SLRP) family along with biglycan. Found in the interterritorial region of cartilage, decorin interacts with collagen and other matrix proteins to regulate the cartilaginous matrix. It has been shown to interact with fibronectin, thrombospondin, C1q, epidermal growth factor receptor (EGFR), and TGF beta. It is believed that decorin also plays a role in the cell cycle of chondrocytes
  
  
• Lefty
  During vertebrate embryogenesis, a left-right axis is established. Secreted growth factors of the TGF-beta family, including gene products derived from nodal, lefty-1 and lefty-2, play crucial roles in establishing left-right asymmetries. TGF-beta (Transforming growth factor-beta) is a pleiotropic cytokine that regulates growth and differentiation of diverse types of cells. TGF-beta actions are directed by ligand-induced activation of TGF-beta receptors. Complexes formed move into the nucleus, where they act as components of a transcriptional complex. Lefty, a novel member of the TGF-beta superfamily, inhibits TGF-beta signaling. Lefty acts to inhibit phosphorylation of Smad2 following activation of the TGF-beta receptor. Lefty also inhibits events downstream from R-Smad phosphorylation. Lefty provides a repressed state of TGF-beta-responsive genes. The Lefty family is comprised of Lefty 1 and Lefty 2 in mouse, and Lefty A and Lefty B in humans. Members of the TGF-beta superfamily require processing for their activation. Cleavage is therefore an essential step for Lefty activation. Lefty is synthesized as a large inactive precursor (41 Kda) that must be endoproteolytically processed to release the bioactive polypeptide (28 kDa and 34 kDa forms). The 28kDa form induces MAPK activity.
  
  
• Smad2
  Smad2 is a 58 kDa member of a family of proteins involved in cell proliferation, differentiation and development. The Smad family is divided into three subclasses: receptor-regulated Smad's, activin/TGFâ receptor-regulated (Smad2 and 3) or BMP receptor regulated (Smad1, 5, and 8); the common partner, (Smad4) that functions via its interaction to the various Smad's; and the inhibitory Smad's, (Smad6 and Smad7). Smad2 consists of two highly conserved domains, the N terminal Mad homology (MH1) and the C-terminal Mad homology 2 (MH2) domains. The MH1 domain binds DNA and regulates nuclear import and transcription while the MH2 domain conserved among all the Smad's regulates Smad2 oligomerization and binding to cytoplasmic adaptors and transcription factors. Activated Smad2 associates with Smad4 and translocates as a complex into the nucleus, allowing its binding to DNA and transcription factors. This translocation of Smad2 (as well as Smad3) into the nucleus is a central event in TGF beta signaling. Phosphorylation of threonine 8 in the calmodulin binding region of the MH1 domain by extracellular signal regulated kinase 1(ERK 1) enhances Smad2 transcriptional activity, which is negatively regulated by calmodulin. The regulation of Smad2 phosphorylation
  
  
• Thrombospondin
  Thrombospondin 2 is an adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions. It can bind to fibrinogen, fibronectin, laminin and type V collagen. This protein has been shown to function as a potent inhibitor of tumor growth and angiogenesis. Studies of the mouse counterpart suggest that this protein may modulate the cell surface properties of mesenchymal cells and be involved in cell adhesion and migration.
  
  
• Phospho T8 (Smad2 )
  Smad2 is a 58 kDa member of a family of proteins involved in cell proliferation, differentiation and development. The Smad family is divided into three subclasses: receptor-regulated Smad's, activin/TGFâ receptor-regulated (Smad2 and 3) or BMP receptor regulated (Smad1, 5, and 8); the common partner, (Smad4) that functions via its interaction to the various Smad's; and the inhibitory Smad's, (Smad6 and Smad7). Smad2 consists of two highly conserved domains, the N terminal Mad homology (MH1) and the C-terminal Mad homology 2 (MH2) domains. The MH1 domain binds DNA and regulates nuclear import and transcription while the MH2 domain conserved among all the Smad's regulates Smad2 oligomerization and binding to cytoplasmic adaptors and transcription factors. Activated Smad2 associates with Smad4 and translocates as a complex into the nucleus, allowing its binding to DNA and transcription factors. This translocation of Smad2 (as well as Smad3) into the nucleus is a central event in TGF beta signaling. Phosphorylation of threonine 8 in the calmodulin binding region of the MH1 domain by extracellular signal regulated kinase 1(ERK 1) enhances Smad2 transcriptional activity, which is negatively regulated by calmodulin. The regulation of Smad2 phosphorylation on threonine 8 by ERK 1 and calmodulin is critical for Smad2 mediated signaling.
  
  
• WNT
  APCBeta Catenin
  The distinct peripheral cytosolic proteins, alpha, beta and gamma catenin (102, 94 and 86 kDa) are found in many tissues bind to the conserved cytoplasmic tail domain of the cell adhesion cadherins. Catenins link E cadherin to other integral membrane or cytoplasmic proteins and are modulated by Wnt1 proto oncogene. The central core region of beta catenin is involved in mediation of cadherin catenin complex interaction with EGFR. Beta-Catenin-mediated signalling is involved at several stages of vertebrate neural development.
  
  
• GSK3
  Glycogen synthase kinase 3 (GSK3) is a proline directed serine threonine kinase that was initially identified as a phosphorylating and inactivating glycogen synthase. GSK3 has been implicated in fundamental cell processes such as cell fate determination, metabolism, transcriptional control, and oncogenesis. Two isoforms, alpha (GSK3A; OMIM 606784) and beta, show a high degree of amino acid homology within their catalytic domains. GSK3B is involved in energy metabolism, neuronal cell development, and body pattern formation.
  
  
• LR5
  The Toll like receptor (TLR) family in mammal comprises a family of transmembrane proteins characterized by multiple copies of leucine rich repeats in the extracellular domain and IL1 receptor motif in the cytoplasmic domain. Like its counterparts in Drosophila, TLRs signal through adaptor molecules and could constitute an important and unrecognized component of innate immunity in humans. The TRL family is a phylogenetically conserved mediator of innate immunity that is essential for microbial recognition. TLRs characterized so far activate the MyD88/interleukin 1 receptor-associated kinase (IRAK) signaling pathway. Toll-like receptor 5 (TLR5) expression is upregulated following exposure to bacteria or to the TLR5 agonist, flagellin. Gram-negative bacteria, stimulate monocyte/macrophage cells in a TLR5-specific, CD14-independent manner. The TLR5 receptor thus appears to be the principal means by which the innate immune system recognizes flagellated bacterial pathogens
  · LR6Wnt3a

• CDX2
  CDX2 is a caudal type homeobox gene that encodes an intestine-specific transcription factor that is expressed early in intestinal development and may be involved in the regulation of proliferation and differentiation of intestinal epithelial cells. It is expressed in the nuclei of epithelial cells throughout the intestine, from duodenum to rectum. The CDX2 protein is expressed in primary and metastatic colorectal carcinomas and has also been demonstrated in the intestinal metaplasia of the stomach and intestinal-type gastric cancer, while it is not expressed in the normal gastric mucosa. Studies have shown that CDX2 is superior marker compared to CK20.
  
  
• SOX9
  SOX9 is a member of the family of SOX (Sry-type highmobility group box) genes that were first identified on the basis of region with high homology to that of Sry (Sex determiningregion Y). SOX9 is a transcription factor with a high mobility group DNA-binding domain that is expressed in all prechondrocytic and chondrocytic cells during embryonic development in a pattern that close parallels that of the gene for type II collagen. SOX9 is important in neural crest formation, and is involved in regulating subsequent epithelial-mesenchymal transition and migration
  
  
• TBR/Eomes
  Tbr2 (t box brain 2) is a a T-zone transcription factor that is expressed by intermediate progenitor cells (IPCs) during development. IPCs are a transitional phase cell arising from radial glia. IPCs divide within the ventricular zone (VZ) or subventricular zone (SVZ) and produce a strictly neuronal population. IPCs can be characterized by expression of Tbr2 and by concurrent downregulation of Pax6, which is expressed by radial glia. A Pax6-Tbr2-Tbr1 expression sequence marks cells as they pass from radial glia to IPC to neurons.
  
  Tbr2 expression is observed in neuron progenitor compartments in development (the subventricular zone and ventricular zone) and expression rises and falls with cortical plate neurogenesis. Transition from radial glia to intermediate progenitor cell is associated with upregulation of Tbr2.