Kinase Family SCYL

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Kinase Classification: Group Other: Family SCYL

SCYL (SCY1) is a family of pseudokinases found in almost all eukaryotes, involved in trafficking of secretory proteins, nuclear tRNA export, and chromosome biology.

Classification and Evolution

SCYL kinases are found in all eukaryotes examined. The family is named after the SCY1 gene of yeast (SCYL = SCY1-Like). There are three subfamilies: SCYL2 is found throughout eukaryotes (other than kinetoplastids), SCYL1 in plants and unikonts (animals, fungi, Dictyostelium) and SCYL3 in most eumetazoans.

Domain Structure

All SCYL have an N-terminal kinase domain and a longer C-terminal region which has weak sequence similarity within and between subfamilies. Much of this region is covered by a Pfam-B domain (Pfam-B_17727), and many members show an array of HEAT repeats and a coiled-coiled region that may be a homodimerization domin [1]. SYCL3 genes have an N-terminal myristoylation site and mammalian SCYL1 genes have a RKLD COPI-interacting motif at the extreme C terminus.


Protein Trafficking

SCYL1 binds COP1 vesicles that mediate retrograde Golgi-to ER transport, through an SCYL1-specific RKLD motif at the extreme C terminus [2]. Knockdown of SCYL1 disrupts Golgi morphology and blocks retrograte COPI-mediated transport from Golgi to ER [3]. The Golgi-localized Gorab protein (aka NTKL-BP1, SCYL-BP1) was found as a interactor of mouse Scyl1 by Y2H and coIP [4]. The yeast SCYL1, Cex1, also has several trafficking-associated physical and genetic interactors, including YPT6 (Golgi fusion of late endosome vesicles), COG5 and COG6 (fusion of vesicles to Golgi), several COPI complex members (COP1, SEC27, SEC29, RET2, UBP5 and BRE5 (ER-Golgi transport), and RGP1 and RIC1 (Golgi-to-ER transport) (BioGrid).

SCYL2 appears to act a a different point in trafficking - the endocytosis and trafficking of surface proteins. Human SCYL2 (aka CVAK104) binds clathrin and the plasma membrane adaptor complex, AP2 [5]. Yeast SCYL2 (Cex1) was also found in a genetic screen for modifiers of a clathrin mutant [6].

The other two subfamilies also appear to be involved in late steps of trafficking: Knockdown of SCYL1 or SCYL3 [PACE-1] was found to inhibit vesicle trafficking after endocytosis, in a kinome-wide screen [7]. Additionally, yata (Drosophila SCYL1) was also found in a screen for genes involved in sorting secretory proteins to large dense core vesicles, in the regulated secretion pathways [8]

SCY1 (SCYL2) in yeast is poorly studied, but has been implicated in sterol transport from the cell surface to the ER [9]. SCY1 genetically interacts with GET2 (Golgi-ER transport), UBP3 (ER-Golgi transport) and LSM6 (RNA processing) [10] and physically with SEC2 (GNEF involved in post-Golgi transport) [11].

SCYL1 in neurobiology and aging

The mdf mouse is a model for neuromuscular atrophy. This defect was mapped to a mutation in Scyl1 [12], correlating with the high expression of Scyl1 in neurons, neuromuscular junctions and synapses. Drosophila SCYL1 (yata/CG1973), interacts genetically with APPL, the A-beta amyloid precursor protein [13]. yata mutants had reduced lifespan, small brains and eye vacuolization. Overexpression of APPL could partially rescue these phenotypes, and double mutants had stronger phenotypes. APPL was mislocalized in yata mutants. SCYL1 was also found in an interactome screen of ataxias, binding indirectly to ataxin-1, whose mutants cause spinocerebellar ataxia [14].

Centrosomes and Telomeres

One splice isoform of human SCYL1 (aka NTKL) was found at the centrosomes during mitosis [1]. SCYL1 levels correlated with centrosomal amplification in cancers, and manipulation of SCYL1 caused centrosome abnormalities [15]. A Drosophila cell line screen showed RNAi phenotypes for both SCYL3 (CG1344) and one of two SCYL2 genes (CK1951) to have defects in spindle morphology when knocked down [16]. SCYL1 is also named TEIF (Telomerase transcriptional Elements Interacting Factor) due to its ability to bind DNA and transactivate the hTERT telomerase and DNA polymerase beta genes [17, 18]. In addition, SCYL2 was found in a proteomic analysis of a telomerase-associated complex [19].

tRNA Export

Human SCYL1 functions in nuclear export of tRNAs [20]. It binds tRNAs, interacts with the nuclear pore through Nup98, and copurifies with a complex of exportin-t (XPOT), exportin-5 (XPO5), RanGTP, and eEF-1A which transports aminoacyl-tRNAs to the ribosomes. Arabidopsis SCYL1 (At2g40730, CTEXP) was also shown to be involved in tRNA export. It binds tRNAs, RanGTP, the exportin-t (PAUSED), and associates with the nuclear pore (Johnstone et al,, doi:10.1139/B10-090). In both human and Arabidopsis, the Ran association is GTP-dependent. A similar story is seen with yeast Cex1 (SCYL1), interacting with aminoacyl tRNAs, Nup116, eEF1A, and Ran (Gsp1) [21, 22].

An ataxia interactome screen [23] confirmed the Nup98 interaction and showed interaction with RANBP16/XPO7, another protein involved in RNA export from the nucleus. The C. elegans SCYL1, W07G4.3 also interacts with XPO7 (C35A5.8) [24]. On a related note, intreactome screens indicate that yeast SCY1 (an SCYL2) interacts with NOB1, and human SCYL2 interacts with NOP56, both involved in ribosome biogenesis

SYCL3 functions

SCYL3 (PACE-1) has a conserved N-terminal myristoylation motif. Human SCYL3 is found in two subcellular locations: on the cytoplasmic face of the Golgi apparatus, dependent on the myristoylation motif, and in lamellipodia, where it may associate with ezrin, a cytoskeletal linker protein. The ezrin association was found by Y2H screening, and maps to the C-terminal regions of both proteins [25].


RNAi screens found yata to be involved in cell size regulation [26].

Regulation and Activity

All SCYL proteins appear to be pseudokinases, as they have lost all three main catalytic residues, K72, D166 and D184, though the changes are conserved (K72F, D166N and D184G for all three human proteins) [27]. Human SCYL2 was shown to bind ATP and auto- and trans-phosphorylate in vitro in one study [5]. However, tagged SCYL3 constructs also showed in vitro kinase activity [25], but this was associated with the non-catalytic C-terminus, required an N-terminal myristoylation motif and could be eliminated with stringent purification methods, suggesting that SCYL3 (and maybe other SCYL) can bind an active kinase rather than having intrinsic kinase activity. All three human SCYL have several phosphorylation sites, and SYCL3 has a T-153 site that is within the putative activation loop, but no upstream kinases are known. Yeast SCY1 also has two phosphorylation sites in the C-terminus (


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All Medline abstracts: PubMed | HubMed