Table 1 Regulators of CLK proteins

SRSF1

Downstream of CLK1

Hyperphosphorylation

Hyperphosphorylation of SRSF1 by CLK1 furtherly facilitated the binding of SRSF1 to Ron ESE

²⁵

Downstream of CLK2

Phosphorylation

Downregulated CLK2 expression decreased the phosphorylation status of SRSF1to inhibit its splicing function

^41,42

Downstream of CLK3

Splicing modulation

CLK3 strongly affected HMGA2 isoforms switching in an SRSF1-dependent manner

⁴³

SRSF2

Downstream of CLK1

Splicing modulation

CLK1 inhibition decreased SRSF2 expression and downregulated CLK1-dependent SRSF2 splicing activity in gastric cancer cells

⁴⁰

SRSF4 and SRSF6

Downstream of CLK1

Phosphorylation

CLK1(Clk/Sty) phosphorylated SRSF4 and SRSF6 during insulin stimulation resulting in exon 17 inclusion and elevated expression of PKCβII

⁵

SRSF5

Downstream of CLK1

Phosphorylation at Ser250

CLK1 promoted alternative splicing of METTL14 and Cyclin L2 in pancreatic cancer

⁴⁴

SRSF10

Downstream of CLK1

Phosphorylation at Ser129, 131 and 133

CLKs modulated the tumorigenic activity of SRSF10 in human colorectal cancer cells

⁴⁵

SPF45

Downstream of CLK1

Phosphorylation at eight serine residues

CLK1 enhanced SPF45-induced Fas mRNA exon 6 exclusion

Inhibition of CLK1 promoted SPF45 degradation via proteasome-dependent proteolysis

^46,47

U1–70K

Downstream of CLK1

Phosphorylation at Ser226

Facilitated U1–70K released from subnuclear granules and subsequent interaction with U1 snRNP and SRSF1

⁴⁸

RBFOX2

Downstream of CLK2

Splicing modulation

Mediated mesenchymal-type ENAH splicing at exon 11a

⁴²

PTP-1B

Downstream of CLK1/2

Phosphorylation at Ser50

Activated PTP-1B and modulated the enzymatic activity

⁴⁹

B56β

Downstream of CLK2

Phosphorylation

Phosphorylation of B56β by CLK2 leads to AKT dephosphorylation at Ser473 and Thr308 sites

^50,51

PGC-1α

Downstream of CLK2

Phosphorylation at 11 serine residues on SR domain

Disrupted the PGC-1α–MED1 interaction and reduced MED1 recruitment to PPARα/PGC-1α promoter resulting in decreased fatty acid oxidation

CLK2 phosphorylated the SR domain of PGC-1α to repress PGC-1α transcriptional activity on gluconeogenic genes in hepatic gluconeogenesis

^49,50

^22,50

USP13

Downstream of CLK3

Phosphorylation at Y708

Promoted USP13 binding with c-Myc, resulting in the activation of purine metabolic gene transcription in CCA

¹²⁴

NEXN

Downstream of CLK4

Phosphorylation at Ser437

CLK4 phosphorylated NEXN at Ser437 to participate in cardiac function regulation

⁵⁶

MITF

Downstream of CLK4

Phosphorylation at Tyr360

CLK4 phosphorylated MITF at Tyr360 to promote the degradation of MITF

¹²⁶

Aurora B

Downstream of CLKs

Phosphorylation at Ser331

Activated Aurora B during late cytokinesis in normally segregating cells

²

AKT

Upstream of CLK1

Phosphorylation CLK1 at SR domain (Ser36, Thr122 and Ser139)

AKT phosphorylated the SR domain of CLK1

⁵³

Upstream of CLK2

Phosphorylation CLK2 at Ser34, Thr127 and Thr343

AKT bond and phosphorylated CLK2 at Ser 34 and Thr 127 in response to ionizing radiation

AKT phosphorylated CLK2 at Thr343 in response to insulin stimulation in hepatic gluconeogenesis

^50,51,52

Insulin stimuli

Upstream of CLK2

Phosphorylation CLK2 at Ser342 and Thr343

CLK2 kinase activity was induced by insulin at Ser342/Thr343 in hepatic gluconeogenesis

⁵⁰

miR-573

Upstream of CLK2

Regulator

miR-573 bond directly with CLK2 and significantly inhibited the expression of CLK2

¹²¹

14–3–3τ

Upstream of CLK2

Regulator

14–3–3τ bond with CLK2 to prevent the proteasomal degradation of CLK2 and increase protein stabilization in glioma stem cells

⁵⁵

c-Myc

Upstream of CLK3

Transcriptional activator

c-Myc overexpression enhanced CLK3 expression

¹²⁴

miR-144

Upstream of CLK3

Regulator

miR-144 post-transcriptionally regulated CLK3 to suppress Wnt/β-catenin signaling in hepatocellular carcinoma

¹²⁵

MITF

Upstream of CLK4

Regulator (Feedback loop)

MITF bond to the E-boxes in the CLK4 promoter to reduce CLK4 transcript expression in ESCC

¹²⁶