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Morphogen-Induced Platelet Activation and Cell Signalling Proc Indian Natn Sci Acad 80 No. 1 March 2014 pp. 77-81 © Printed in India. 10.16943/ptinsa/2014/v80i1/55087 Review Article Morphogen-induced Platelet Activation and Cell Signalling R L MALLICK and D DASH* Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India (Received 17 November 2013; Revised 26 January 2014; Accepted 28 January 2014) 1. Introduction Platelets are unique cellular effectors of hemostasis and thrombosis. They are one of the Morphogens are signalling molecules that act directly important contributors to thrombotic disorders. These on cells to produce specific cellular responses. This cells act rapidly in concert with coagulation proteins term was originally put forward by Turing (1952) who and other vascular cells. During biogenesis, platelets also described its chemical basis. Most of these are generated as cytoplasmic buds from precursor secreted proteins signal between the cells. Wolpert bone marrow megakaryocytes. Therefore, they are (1969) first reported a role of morphogen in cell morphologically devoid of nucleus and have no signalling. The roles of several morphogens (e.g., DNAs, and thus are incapable of transcribing nuclear Transforming Growth Factor- (TGF- ), Hedgehog/ material. In general, the transcriptional activity ramps Sonic Hedgehog, Wingless (Wnt) signalling, up in individual megakaryocytes as they prepare to Epidermal Growth Factor (EGF), Fibroblast Growth generate and release thousands of platelets (Patel et Factor (FGF), and Retinoic Acid (RA) in signal al., 2005). Therefore, these terminally differentiated transduction have been studied by scientists in several blood cells possess megakaryocyte-derived cell lineages. Assoian et al. (1983) identified major messenger RNAs (mRNAs) that have recently been storage sites of TGF- in human platelets. Xie et al. demonstrated to be functional, leading to protein (2003) showed expression of TGF- regulated gene synthesis especially in activated platelets. Therefore, in a mouse mammary gland epithelial cell line. platelets are genetically predetermined cells and Iwasaki et al. (2000) reported that EGF mRNA expression level within them is fixed. Thus, stimulates growth of vascular smooth muscles that it would be interesting to study and elaborate the may be involved in genesis of human vascular disease. morphogen-induced cell signalling events within RA acts as a ligand and diffusible morphogen, the anucleate cells. The present article aims to highlight and review morphogen-induced cell signalling within distribution and levels of which are well controlled platelets and it will be limited to the role of in embryonic tissues by its regulated synthesis and morphogens in platelet biology. breakdown. The occurrence of RA signalling in embryonic development was subsequently reported 2. Morphogen Gradients and Platelets as by Rhinn and Dollé (2012). These cellular events play Responding Cells important roles in regulating the growth, proliferation Morphogens are long-ranging signalling molecules and death of cells. They function in enormously that form a graded distribution across tissues to induce diverse developmental processes, the dysfunction of cellular responses and pattern development in which can lead to pathological consequences. concentration-dependent manner. Cells exposed to *Author for Correspondence: E-mail: [email protected]; Tel: 91-9336910665 78 R L Mallick and D Dash higher levels of morphogen molecules activate motility and apoptosis in most cells. different transcriptional effectors, whereas those Assoian et al. (1983) reported that platelets exposed to lower levels adopt different fates. Thus, express 40-100 fold higher type- TGFs than other the graded morphogen distribution subdivides tissues non-neoplastic cells. Letterio et al. (1998) showed into distinct cell types, which are arranged as a secretion of TGF- by most immune cells including function of their distance from the source (Briscoe et leukocytes. However, platelet-derived TGF- , which al., 2010). Cellular response to morphogen is, is a polypeptide of 25,000 Da, possesses attributes therefore, mainly concentration-dependent. that are different from other platelet proteins in many Morphogens trigger signalling events through aspects. Conventional growth factors directly activation of receptors on their responding cells. Thus, stimulate DNA synthesis to exert their effect whereas expression of related receptors on or within platelets, platelet-derived TGF- acts via non-canonical which can respond to morphogen gradients and pathway. TGF- is weakly mitogenic whereas PDGF trigger platelet signalling would be highly impactful. is a potent mitogen. Moreover, it is different from Various studies have recently demonstrated presence other platelet-associated chemokines such as of such specific receptors on platelet surface. For connective tissue activating peptide-III (CTAP-III), example, Lev et al. (2007) identified presence of platelet factor 4 and -thromboglobulin. Due to these functional TGF- receptor on platelets. Steele et al. unusual biological properties, platelet-derived (2009) reported that Wnt signalling negatively TGF- is considered as a unique mitogen. regulates platelet function. In addition, role of platelet-derived growth factors (PDGF) in physiology 4. Existence of Wnt Signalling Pathway in Platelets and medicine is well described by Andrae et al. (2008). Moraes et al. (2007) put forward non-genomic Multi-cellular organisms undergo activation of signalling pathway of retinoid X receptor through evolutionarily conserved signalling pathways, which binding and inhibiting G protein-coupled receptors include Wnts, Bone Morphogenic Proteins (BMPs) and Hedgehogs (Hh) during development. It occurs (Gq) in human blood platelets. These studies have boosted an interest towards occurrence of in a highly coordinated manner to ensure proper morphogen-induced cellular events within human patterning of embryo. Upon release of these signalling blood platelets. molecules, cell populations induce intracellular signalling events in adjacent cells. 3. Existence of TGF- and PDGF as Morphogens for Responding Platelets Wnt signalling plays a key role in maintenance of stem cell pluripotency during adult homeostasis. TGFs are biologically active peptides. They induce Wnts comprise a large family of secreted proteins anchorage dependent, non-neoplastic cells to lose acting as ligands. Logan and Nusse (2004) showed contact inhibition and undergo anchorage- that Wnts affect diverse cellular processes leading to independent growth. TGFs are classified into two embryonic induction, generation of cell polarity and types, type-â and type- , based on their relationship specification of cell fate. Wnt signalling is required with EGFs. Type-â TGFs are single chain, low in most embryonic developmental processes in both molecular weight (Mr < 10,000) peptides that are vertebrates and invertebrates. Wnt signalling has been defined by an ability to compete with 125I-labelled classified into canonical and non-canonical EGFs for binding to EGF cell surface receptor. In pathaways (Veeman et al., 2003). In canonical Wnt contrast, Type- TGFs do not bind to EGF receptor signalling pathway, binding of Wnt to frizzled and but they require EGF or TGF-â to express their LRP5/6 co-receptors leads to Wnt-dependent biological activity. Type- TGFs play essential roles inhibition of glycogen synthase kinase-3 (GSK-3 ) in various cellular processes including early that results in stabilization of -catenin and facilitates embryonic development, cell growth, differentiation, translocation of the stabilized -catenin into nucleus Morphogen-induced Platelet Activation and Cell Signalling 79 affecting transcription of target genes. Clevers and signalling components are present in human platelets. Battle (2006), Iwasaki et al. (2000) and Krishnan et Sustained aggregation of platelets for 15 minutes in al. (2006) independently observed that uncontrolled presence of extracellular calcium was associated with canonical Wnt signalling pathway is hallmark of nearly complete proteolysis of -catenin. -catenin cancer and other degenerative diseases. Therefore, cleavage was attributed to peptidase activities of regulatory mechanisms that control Wnt signalling calpain and proteasome, where integrin IIb 3 are of crucial importance. In non-canonical Wnt engagement and protein kinase C were other major signalling pathway, binding of Wnt to frizzled players in stabilization of -catenin. In another study, receptors does not involve GSK-3 or -catenin Kim et al. (2011) demonstrated that Wnt5a potentiates stabilization. Overexpression of ligands (Wnt5a or U46619 induced rat platelet aggregation via Wnt11) for non-canonical pathways causes an activation of PI3K/Akt signalling. Therefore, platelets increase in intracellular calcium without affecting - respond to various canonical and non-canonical Wnt catenin level. It occurs due to activation of calcium/ ligands in distinctive manner. calmodulin-dependent kinase II (CAMKII) and protein kinase C (PKC). Some frizzled receptors can 5. Epidermal Growth Factors (EGFs) and Platelet also activate heterotrimeric G proteins to activate Biology phosphodiesterase and phospholipase C (PLC) that EGF is a naturally occurring molecule capable of causes an increase in intracellular calcium level. stimulating cellular growth, proliferation and differentiation. It binds to epidermal growth factor Platelet aggregation is a major process of receptor (EGFR)
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