Impact of SULF1 Gene on Angiogenesis.
Impact of SULF1 Gene on Angiogenesis. Single-gene disorders occur when mutation in a gene causing alteration of gene function; while in multifactorial disorders, mutations occur in multiple genes, and these are usually coupled with environmental causes. In addition, in a multifactorial disorder such as diabetes, the complication is under the influence of different genes. For example, in diabetic retinopathy many genes are involved including genes related to angiogenesis. One of these genes is SULF1. Studying the function and molecular bases of the mutations in these genes plays an important role in understanding the pathology of diseases . And is helpful in management, treatment and even prevention of them.
It has been identified that SULF1 can interfere in signaling of many heparan binding growth factors and morphogens. Heparan sulfate (HS) proteoglycans are glycoproteins which regulate many signaling pathways. HS is added to proteins during Golgi modifications. Sulfatase 1 is a catalytic enzyme which removes sulfate groups from HS of proteoglycans. The angiogenesis-related studied molecules which can be regulated by heparan sulfate including VEGF, FGF, Wnt, BMP, HGF, HB-EGF and SHH. In this review, we have focused on the role of these signaling molecules on angiogenesis and the role of SULF1 in their regulation.
Introduction, Impact of SULF1 Gene :
According to “Impact of SULF1 Gene on Angiogenesis” Heparan sulfate (HS) proteoglycans are glycoproteins containing heparan sulfate groups (1, 2), which are anchor site for a broad variety of signaling proteins and regulate many signaling pathways and functions (3). During post-translational modification, Golgi apparatus adds heparan sulfate units to proteins (4); which is essential for normal embryonic development and play crucial role in regulating key developmental signaling pathways. This requirement is due to the obligatory role for HS in signaling pathway of many growth factors and morphogens that bind to sulfated domain in the HS polymer chain. The sulfation patterning of HS is determined by a complex of sulfotransferases and endosulfatases that transfer and remove 6-O-sulfate of the HS (5, 6). Before the identification of quail orthologous of SULF1, heparan sulfatases considered unchanged during life.
The discovery showed that alteration of heparan sulfate binding affinity to signaling molecules is due to the change in binding sites of heparan sulfate groups. SULF1 is homologous with lysosomal N-acetyl glucosamine sulfatases (G6- sulfatases), which catalyze the hydrolysis of 6- O-sulfates from N-acetyl glucosamines of heparan sulfate during the degradation of HSPGs. In contrast to its lysosomal homolog, the enzyme is located in cell surface and is active in neutral PH (7). Shortly, orthologs of QSULF1 were found in human and murine and named HSULF1 and MSULF1, respectively. The paralog of HSULF1, called HSULF2 was identified with 63% to 65% homology to HSULF1(8).