HB-GAM belongs to the pleiotrophin family. During embryonic and early postnatal development, HB-GAM is expressed in the central and peripheral nervous system and also in several non-neural tissues, notably lung, kidney, gut and bone. While in the adult central nervous system, it is expressed in an activity-dependent manner in the hippocampus where it can suppress long term potentiation induction. HB-GAM has a low expression in other areas of the adult brain, but it can be induced by ischemic insults, or targeted neuronal damaged in the entorhinal cortex or in the substantia nigra pars compacta. It is structurally related to midkine and retinoic acid induced heparin-binding protein and has a high affinity for heparin. HB-GAM binds anaplastic lymphoma kinase (ALK) which induces MAPK pathway activation, an important step in the anti-apoptotic signaling of PTN and regulation of cell proliferation. It also functions as a secreted growth factor and induces neurite outgrowth and which is mitogenic for fibroblasts, epithelial, and endothelial cells.
Placenta growth factor (PlGF) is a member of the PDGF/VEGF family of growth factors that share a conserved pattern of eight cysteines . Alternative splicing results in at least three human mature PlGF forms containing 131 (PlGF-1), 152 (PlGF-2), and 203 (PlGF-3) amino acids (aa) respectively . Only PlGF-2 contains a highly basic heparin-binding 21 aa insert at the C-terminus . Human PlGF-1 shares 56%, 55%, 74% and 95% aa identity with the comparable isoform of mouse, rat, canine, and equine PlGF, respectively. PlGF is mainly found as variably glycosylated, secreted, 55-60 kDa disulfide linked homodimers . Mammalian cells expressing PlGF include villous trophoblasts, decidual cells, erythroblasts, keratinocytes, and some endothelial cells . Circulating PlGF increases during pregnancy, reaching a peak in mid-gestation, this increase is attenuated in preeclampsia . However, deletion of PlGF in the mouse does not affect development or reproduction. Postnatally, mice lacking PlGF show impaired angiogenesis in response to ischemia . PlGF binds and signals through VEGF R1/Flt-1 but not VEGF R2/Flk-1/KDR, while VEGF binds both but signals only through the angiogenic receptor, VEGF R2. PlGF and VEGF therefore compete for binding to VEGF R1, allowing high PlGF to discourage VEGF/VEGF R1 binding and promote VEGF/VEGF R2-mediated angiogenesis . However, PlGF (especially PlGF-1) and some forms of VEGF can form dimers that decrease the angiogenic effect of VEGF on VEGF R2 . PlGF-2, but not PLGF-1, shows heparin-dependent binding of Neuropilin (Npn)-1 and Npn-2 . PlGF induces monocyte activation, migration, and production of inflammatory cytokines and VEGF. These activities facilitate wound, bone fracture, and cardiac repair, but also contribute to inflammation in active sickle cell disease and atherosclerosis . PlGF can also inhibit TIMP3 expression in the spleen, leading to immune triggering of hypertension .
Serine / threonine-protein kinase PLK1 / PLK-1, also known as polo-like kinase 1 (PLK-1) or serine / threonine-protein kinase 13 (STPK13), Polo-like kinases (PLKs), is a family of four serine / threonine protein kinases that are critical regulators of cell cycle progression, mitosis, cytokinesis, and the DNA damage response. PLK1 / PLK-1 is ubiquitously expressed. The mRNA and protein expression of PLK1 / PLK-1, -2 and -4 are coordinately regulated during cell cycle progression, but PLK3 levels are independent of the other three family members. PLK1 / PLK-1 is the most well characterized member of this family and strongly promotes the progression of cells through mitosis. During the various stages of mitosis PLK1 / PLK-1 localizes to the centrosomes, kinetochores and central spindle. Serine / threonine-protein kinase that performs several important functions throughout M phase of the cell cycle, including the regulation of centrosome maturation and spindle assembly, the removal of cohesins from chromosome arms, the inactivation of APC / C inhibitors, and the regulation of mitotic exit and cytokinesis. It is required for recovery after DNA damage checkpoint and entry into mitosis. PLK1 / PLK-1 is required for kinetochore localization of BUB1B, spindle pole localization of isoform 3 of SGOL1 and plays a role in regulating its centriole cohesion function. PLK1 / PLK-1 Phosphorylates BORA, and thereby promotes the degradation of BORA. PLK1 / PLK-1 also contributes to the regulation of AURKA function and phosphorylates SGOL1.
PNLIP is an enzyme which belongs to the lipase family. Secreted from the pancreas, PNLIP is the primary lipase that hydrolyzes dietary fat molecules in the human digestive system, converting triglyceride substrates found in ingested oils to monoglycerides and free fatty acids. Bile salts secreted from the liver and stored in gallbladder are released into the duodenum where they coat and emulsify large fat droplets into smaller droplets, thus increasing the overall surface area of the fat, which allows the lipase to break apart the fat more effectively. The resulting monomers (2 free fatty acids and one 2-monoacylglycerol) are then moved by way of peristalsis along the small intestine to be absorbed into the lymphatic system by a specialized vessel called a lacteal.
Phospholipid transfer protein, also known as Lipid transfer protein II and PLTP, is a secreted protein which belongs to theBPI/LBP/Plunc superfamily and BPI / LBP family. PLTP is nearly ubiquitously expressed in cells and tissues. PLTP converts HDL into larger and smaller particles. It may play a key role in extracellular phospholipid transport and modulation of hdl particles. High-density lipoproteins (HDL) play a major protective role against the development of coronary artery disease. PLTP is a main factor regulating the size and composition of HDL in the circulation and plays an important role in controlling plasma HDL levels. This is achieved via both the phospholipid transfer activity of PLTP and its capability to cause HDL conversion. PLTP is one of the key lipid transfer proteins in plasma and cerebrospinal fluid. It is involved in novel intracellular functions. PLTP is an important modulator of lipoprotein metabolism, including interparticle phospholipid transfer, remodeling of HDL, cholesterol and phospholipid efflux from peripheral tissues, and the production of hepatic VLDL. PLTP also plays an important role in inflammation and oxidative stress. Accordingly, PLTP has also been implicated in the development of atherosclerosis.
Phosphomannomutase 1 (PMM1) blongs to the eukaryotic PMM family. Phosphomannomutase 1 can catalyzes the conversion between D-mannose 6-phosphate and D-mannose 1-phosphate which is a substrate for GDP-mannose synthesis. GDP-mannose is used for synthesis of dolichol-phosphate-mannose which required for a number of critical mannosyl transfer reactions. PMM1 is highly expressed in liver, heart, brain, and pancreas, but lower expression in skeletal muscle. In addition, PMM1 may be responsible for the degradation of glucose-1,6 bisphosphate in ischemic brain.
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