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Based on the way of mechanism of FGF actions, we can classify FGF activities into three types: intracrine, paracrine, and endocrine.
FGF Paraclete subfamilies include FGF1, FGF2, 3, 7, 10 and 22, FGF22, 4, 5, 6, 8, 17, 9, 16, 20 etc. Almost all the FGF family members possess an N terminal secretory signal pep tide which is cleanable and for exporting through the ER and Golgi apparatus pathway. Though, there is no presence of secretory signal peptide in FGF 1 and 2 and are represented to be shown as exporting from the cells by the independent method of conventional ER – Golgi apparatus pathway. A classical secretory pathway is shared by the subfamily FGF9 members, but they don’t possess a cleavable signal sequence. Rather, they have a secretory signal sequence which is bipartite in nature to interact with the secretory machinery. All the FGF paracrine bind themselves with HS strongly and a glycosaminoglycan in the pericellular and the extracellular matric, binds them at binding sites of heparin. Thus as result of this interaction, their diffusion radius limits so much that all the FGFs start exerting biological impacts surrounding the synthesis source.
FGF intracrine are FGF 11 subfamily members which are found as intracellular protiens in the cells. FGFs intracrine are said to play an important role in the excitability regulation of the granular neurons. The members of FGF19 don’t bind to HS or if they do it very weak, hence they function in the endocrine manner. See more about : Strategic Management Assignment Help
HS is bound by only FGF paracrine. There are several experimental systems which shows the FGF transport is controlled by HS. For eg, the mutations in SGL (gene coding sugarless) and SFL 9Sulfateless,which are often found to be indispent in the heparin sulfate chain biosynthesis, were recognized to be showing phenotyope to WG (Wingless) or Hh (Hedgehog) signalling the mutants.The FGF diffusion is regulated by the HS interaction taking place in the extracellular matrix, thus the form of concentration gradients of FGF is determined, along with the FGF release and storage.The GF (growth factor)/ morphogen type signals which FGF generates, need the assembly of the FGF ternary ligand complex, HS and FGFR (receptor) by which both receptors and ligands are engaged. Hence, HS works as the co – receptor.Read more about : Robot Technology Assignment Help
Evolution of the FGF Gene Family
There is no evidence of presence of FGF genes in the unicellular organisms ( E. coli, Saccharomyces cerevisiae). Two (egl – 17 and let – 756) and three FGF genes ( branch – less, pyramus and thisbe) were found and identified after performing the genome sequencing Drosophila and Caenorhabditis elegans. Later, based on genome sequencing, there were six more genes found and identified in ascidian Ciona intestinalis, a basal chordate, these are said to be the ancestral genes of FGF subfamilies of human genes, including FGF – 4 like, FGF – 5 like, FGF – 8 like, FGF – 9 like, FGF – 10 likes and FGF – 13 like.
In mouse, human and zebra fish FGF families, so far there have been total 22 FGF genes identified. The FGF gene subfamilies’ ancestral genes resulted in the gene duplication based on a hypothesis which followed the deuterostomes and protostomes divergence. An evolution history model is proposed which presents the two phases of gene expansion. The first phase explains gene duplication which took place due to the FGFgene results from two or more than two genes (3 to 6 genes) during the process of early metalanguage evolution. Second phase explains two large scale genome duplications from which full complement of vertebrate genes were generated.
The ancestral gene inthe entire FGF family is FGF 13 – like gene. Gene duplication generated the FGF 4- like gene at a very early stage from the FGF 13 – like. The gene duplication generated FGF 5 – like, FGF 8 – like, FGF 9 – like, FGF 10 – like and FGF 15/19 – like in first phase. The second phase resulted in the expansion of all FGFs and became three to four members.
Structure molecule info on: FGFs then FGFRs
FGFs: Their molecular weight ranges from scale of 17 to 34 KDa in case of vertebrates while Drosophila has a molecular weight of 84 KDa. There is a similar structural core shared by all of the FGFs with 28 being very conserved, with residues of amino acids with 6 invariants. The X – Ray Crystallography done on FGFs presented a very similar pattern of folding the interleukins IL – !α and IL-1β.
HS: There are repeated units of disaccharides which are joined together by a 1 – 4 linkage bong. The synthesized chains of HS always bind to the core protein for forming the HSPGs (Heparan Sulfate Proteoglyans). HSPG is a core protein which regulates the synthesized chains of HS to bind to their functional sites, including extracellular matrix or cell surface. Heparin is most commonly experimented as an HS proxy,is a more sulfated structure nevertheless.Read more about :Information Technology Strategy Assignment
FGFRs: These are described as immunoglobulin domains i.e. I, II,and III. On the domain I location, the heparin binding location is stained orange. There is a black box which is acid box in between the domain II and domain III. FGF interacts and attaches to the Ig II and FGF ligands bind with the Ig III adjacent surfaces. The portion which is green colored is the second half of spliced immunoglobulin domains III. (TK: tyrosine kinase).
Nanoparticles are transported within the vesicles cells by endocytosis, which depends on the internalization mode. Are either recycled or trafficked back to the cell organelles, which include the golgi mitochondria, golgi and thelysosomes. A complex process of intracellular transport, endosomal trafficking transport protiens within the cells. This process shortens the vesicles and these are dissociated or fused, along with the lysosomes and endosomes.
For the nanoparticles which target he endolysosomal network, like those which are used to treat the lysosomalstorage disorder, the targets are provided with rapid access by endocytic uptake. Though in case of application,the nanoparticles are trapped within the vesicle is always undesirable.Further more, the vesicles mature into the lysosomes and endosomes, which is presented with help iof immediate acidification from the pH scale value of 6 to 4, inside the vesciles and degradative enzymes are employed to digest the content of these vesciles. Nanoparticles are required to be equipped with the methods and mechanisms so that they can escape from the network of endolysome.
Fig 3: Intracellular transport of nanoparticles: Once the internalization is done with help of any of endocytic pathways, these nanoparticles are transported to the endolysomal network using cytoskeletal structures and motor protiens. The vesicle content can be transported to the sortingendosommes, or they can be recycled back to the cell surface suing the plasma membrane fusion process. On the other side, the maturation of endosomes can take place to lysosomes using a luminal acidication using the degradative enzymes so that the degradative vesicle content can be targeted. For accessing the nuclear targets or the cytoplasmic targets, the nanoparticles should be able to escape from the network of endosomes and also be able to traverse back to the crowded cytoplasm.
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