Disease relevance of SYTL1

• These observations decisively prove that Rab27a is involved in CFTR channel regulation through protein-protein interactions involving Munc13-4 and SLP-5 effector proteins, and thus could be a potential target for cystic fibrosis therapy [1].

High impact information on SYTL1

• In this work, we demonstrate that the phosphatidylinositol 3,4,5-trisphosphate-binding protein JFC1 is an ATP-binding protein with magnesium-dependent ATPase activity [2].
• The predicted amino acid sequence of JFC1 denotes a putative nucleotide-binding site similar to those in the GHKL ATPase/kinase superfamily [2].
• Phosphatidylinositol 3,4,5-trisphosphate, a high-affinity ligand of JFC1 did not affect its ATPase kinetics parameters, suggesting that the phosphoinositide have a different role in JFC1 function [2].
• The N-terminal synaptotagmin-like protein (Slp) homology domain (SHD) of the Slp and Slac2 families has recently been identified as a specific Rab27A-binding domain (Kuroda, T. S., Fukuda, M., Ariga, H., and Mikoshiba, K. (2002) J. Biol. Chem. 277, 9212-9218; Fukuda, M., Kuroda, T. S., and Mikoshiba, K. (2002) J. Biol. Chem. 277, 12432-12436) [3].
• JFC1 possesses two C2 domains in tandem [4].

Biological context of SYTL1

• Co-transfection with NF-kappaB expression vectors or stimulation with TNFalpha resulted in significant transactivation of the jfc1 promoter construct, although transactivation of a mutated jfc1 promoter was negligible [5].
• The jfc1 promoter was transcriptionally active in various cell lines, as determined by luciferase reporter assays following transfection with a jfc1 promoter luciferase vector [5].
• The human promoter region of JFC1, a phosphatidylinositol 3,4,5-trisphosphate binding ATPase, was isolated by amplification of a 549 bp region upstream of the jfc1 gene by the use of a double-PCR system [5].
• Although the SHD of Slp4-a interacts with three distinct Rab species (Rab3A, Rab8A, and Rab27A) in vitro, in contrast to other Slp members, which only recognize Rab27 isoforms, Slp4-a functions as a Rab27A effector during DCV exocytosis under physiological conditions [6].
• Akt regulates the subcellular localization of the Rab27a-binding protein JFC1 by phosphorylation [7].

Anatomical context of SYTL1

• JFC1 mRNA was abundantly expressed in bone marrow and leukocytes [4].
• The expression of JFC1 in neutrophils was restricted to the plasma membrane/secretory vesicle fraction [4].
• Exclusive synaptotagmin-like staining, therefore, indicated the regions with only dense-core vesicles [8].
• JFC1 and Rab27a colocalize in the proximity of the plasma membrane in LNCaP cells [7].
• Finally, we show that as a consequence of in vivo phosphorylation, JFC1 dissociates from the membrane, promoting JFC1 redistribution to the cytosol [7].

Associations of SYTL1 with chemical compounds

• The Rab27a-binding protein, JFC1, regulates androgen-dependent secretion of prostate-specific antigen and prostatic-specific acid phosphatase [9].
• In contrast to synaptotagmins, JFC1 was unable to bind to inositol 1,3,4,5-tetrakisphosphate but did bind to phosphatidylinositol 3,4,5-trisphosphate and to a lesser extent to phosphatidylinositol 3,4-diphosphate [4].
• By mutagenesis analysis and subsequent immunoprecipitation (IP), we established that Akt phosphorylates JFC1 at serine 241 [7].
• Using the phosphatase and tensin homolog-null LNCaP cells and the phosphatidylinositol 3-kinase inhibitor LY294002, we show that the phosphorylation of endogenous JFC1 is dependent on the phosphatidylinositol 3-kinase/Akt pathway [7].

Regulatory relationships of SYTL1

• Androgen-dependent PSAP secretion was significantly inhibited in cells that expressed the C2A domain of JFC1 [PtdIns(3,4,5)P3-binding-domain], but was unaffected by JFC1 overexpression [9].

Other interactions of SYTL1

• Conversely, PSA secretion was not inhibited by the C2A domain of JFC1 [9].
• JFC1, a novel tandem C2 domain-containing protein associated with the leukocyte NADPH oxidase [4].
• Rab27a regulates epithelial sodium channel (ENaC) activity through synaptotagmin-like protein (SLP-5) and Munc13-4 effector mechanism [10].

Analytical, diagnostic and therapeutic context of SYTL1

• The cell lines PC-3, LNCaP and DU-145, but not Epstein-Barr virus-transformed lymphocytes, showed a dramatic increase in the expression of JFC1 after treatment with TNFalpha, suggesting that transcriptional activation of JFC1 by the TNFalpha/NF-kappaB pathway is significant in prostate carcinoma cell lines [5].
• Using microcapillary high-performance liquid chromatography tandem mass spectrometry, we identified five Akt-phosphorylation sites in JFC1 [7].

References