Role of Fibulins in Embryonic Stage Development and Their Involvement in Various Diseases

Abstract

The extracellular matrix (ECM) plays an important role in the evolution of early metazoans, as it provides structural and biochemical support to the surrounding cells through the cell–cell and cell–matrix interactions. In multi-cellular organisms, ECM plays a pivotal role in the differentiation of tissues and in the development of organs. Fibulins are ECM glycoproteins, found in a variety of tissues associated with basement membranes, elastic fibers, proteoglycan aggregates, and fibronectin microfibrils. The expression profile of fibulins reveals their role in various developmental processes such as elastogenesis, development of organs during the embryonic stage, tissue remodeling, maintenance of the structural integrity of basement membrane, and elastic fibers, as well as other cellular processes. Apart from this, fibulins are also involved in the progression of human diseases such as cancer, cardiac diseases, congenital disorders, and chronic fibrotic disorders. Different isoforms of fibulins show a dual role of tumor-suppressive and tumor-promoting activities, depending on the cell type and cellular microenvironment in the body. Knockout animal models have provided deep insight into their role in development and diseases. The present review covers details of the structural and expression patterns, along with the role of fibulins in embryonic development and disease progression, with more emphasis on their involvement in the modulation of cancer diseases.

Combined proteomic and biochemical analyses redefine the consensus sequence requirement for epidermal growth factor-like domain hydroxylation

“…Our work has identified EGFDs in human fibulins as substrates of AspH-catalyzed asparagine hydroxylation in the ovary, an observation which is of interest considering the importance of fibulins in extracellular matrix biochemistry, including their proposed roles in cancer biology ( 80 , 84 ). Fibulins might be relevant AspH downstream targets transmitting pathophysiologic-relevant effects of AspH upregulation in some cancer cells.…”

“…This approach has been found to improve the identification of hydroxylated proline residues by a factor of ∼9 when compared to use of the MaxQuant software (Max-Planck-Institute of Biochemistry; https://maxquant.org ) ( 78 ). We chose to investigate data from female reproductive tissue as these generally contain high levels of AspH and EGFD-containing proteins that are putative AspH substrates ( 53 , 79 , 80 , 81 ).…”

“…3 and 4 ). Human fibulins 1 to 8 are extracellular matrix–associated secreted glycoproteins that bear multiple EGFDs and have diverse functions in extracellular matrix stabilization and remodeling ( 80 , 84 , 85 ), including in relation to wound healing ( 86 ). EGFDs in human FBLN1 have been previously reported to be hydroxylated; however, the previous report did not specify which asparagine and/or aspartate residues of the multiple EGFDs are hydroxylated and which are not ( 63 ).…”

Proteomes of Extracellular Vesicles From Pancreatic Cancer Cells and Cancer-Associated Fibroblasts

“…Using 50 IPM as an intensity threshold, we focused on proteins that were relatively abundant (≥50 IPM) in the EVs derived from all the PDAC cell lines with >1.5-fold increase in expression compared with HPDE cells. Among the 36 proteins identified, a set of 8 proteins (alpha-2-HS-glycoprotein, 78 apolipoprotein E, 79,80 fibulin-1, 81 aminopeptidase N [ANPEP or CD13], 82 plasminogen, 83 gelsolin, 84 S100-A4, 79 and pigment epithelium-derived factor 84 ) that were previously found to be associated with PDAC is shown in Figure 7. Except for ANPEP (CD13), the remaining proteins showed increased expression in the EVs secreted from PDAC and CAF cell lines relative to HPDE.…”

Impact of EFEMP1 on the survival outcome of biliary atresia in Thai infants

“…In addition, all cases with identified variants had poor surgical outcomes and ended with liver cirrhosis and liver failure. The results of the survival analysis, which showed better native liver survival in BA with the recessive genotype of rs6761893 suggested that EFEMP1 variants might have some defects in biliary tract remodeling during embryonic period 17 or extracellular matrix dysregulation which may results in decreased bile excretion 18 . Although clear explanation about EFEMP1 functions is beyond the scope of our study, these findings indicate that EFEMP1 is an interesting candidate gene that should be further explored for its role in the pathogenesis and severity factor of BA.…”