# Decoding SR protein regulation: kinases, phosphatases, and therapeutic targeting strategies **Authors:** Nasi Liu, Fleur van der Ende, Bob van de Water, Sylvia E. Le Dévédec PMC · DOI: 10.1007/s13402-026-01168-8 · 2026-02-04 ## TL;DR This review explores how SR proteins, which are important for RNA splicing, are regulated by phosphorylation and how targeting this process could lead to new cancer treatments. ## Contribution The paper provides a comprehensive overview of kinase and phosphatase networks regulating SR proteins and their therapeutic implications in cancer. ## Key findings - SR proteins are regulated by phosphorylation and dephosphorylation, which are critical for their function in RNA splicing. - Targeting SR protein phosphorylation could offer new therapeutic strategies for cancer treatment. - Combining SR protein-targeting drugs with other therapies may enhance cancer treatment efficacy. ## Abstract RNA splicing is a fundamental cellular process that transforms precursor messenger RNA (pre-mRNA) into mature messenger RNA (mRNA) by removing non-coding introns and rejoining coding exons. Serine/arginine-rich (SR) proteins, a family of RNA-binding proteins, play crucial roles in RNA splicing by recruiting essential components for spliceosome assembly. The activity of SR proteins is tightly regulated by post-translational modifications, including phosphorylation, acetylation, methylation, and ubiquitination. Among these, the dynamic balance between phosphorylation and dephosphorylation is particularly critical for modulating SR protein function. Given their involvement in cancer, SR proteins represent promising targets for therapeutic intervention. In this review, we provide a comprehensive overview of the current understanding of the regulatory networks involving kinases and phosphatases governing SR protein phosphorylation. We also discuss the existing therapeutic strategies using small-molecule inhibitors aimed at regulating SR protein phosphorylation in the context of cancer. In conclusion, this review highlights the importance of phosphorylation regulation in SR protein function and the RNA splicing process. Targeting SR protein phosphorylation may open new therapeutic avenues or enhance the efficacy of cancer treatments when used in combination with other drugs. ## Linked entities - **Diseases:** cancer (MONDO:0004992) ## Full-text entities - **Genes:** MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, PNISR (PNN interacting serine and arginine rich protein) [NCBI Gene 25957] {aka C6orf111, HSPC306, SFRS18, SRrp130, bA98I9.2}, PPP1CA (protein phosphatase 1 catalytic subunit alpha) [NCBI Gene 5499] {aka PP-1A, PP1A, PP1alpha, PPP1A}, INS (insulin) [NCBI Gene 3630] {aka IDDM, IDDM1, IDDM2, ILPR, IRDN, MODY10}, PTK2B (protein tyrosine kinase 2 beta) [NCBI Gene 2185] {aka CADTK, CAKB, FADK2, FAK2, PKB, PTK}, PPP1R2 (protein phosphatase 1 regulatory inhibitor subunit 2) [NCBI Gene 5504] {aka IPP-2, IPP2, PPP1R2A}, ING2 (inhibitor of growth family member 2) [NCBI Gene 3622] {aka ING1L, ING1Lp, p33ING2}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, COL11A2 (collagen type XI alpha 2 chain) [NCBI Gene 1302] {aka DFNA13, DFNB53, FBCG2, HKE5, OSMEDA, OSMEDB}, AURKA (aurora kinase A) [NCBI Gene 6790] {aka AIK, ARK1, AURA, BTAK, PPP1R47, STK15}, ERH (ERH mRNA splicing and mitosis factor) [NCBI Gene 2079] {aka DROER}, HNRNPA2B1 (heterogeneous nuclear ribonucleoprotein A2/B1) [NCBI Gene 3181] {aka HNRNPA2, HNRNPB1, HNRPA2, HNRPA2B1, HNRPB1, IBMPFD2}, TRA2A (transformer 2 alpha homolog) [NCBI Gene 29896] {aka AWMS1, HSU53209}, TTK (TTK protein kinase) [NCBI Gene 7272] {aka CT96, ESK, MPH1, MPS1, MPS1L1, PYT}, PRPF4 (pre-mRNA splicing tri-snRNP complex factor PRPF4) [NCBI Gene 9128] {aka HPRP4, HPRP4P, PRP4, Prp4p, RP70, SNRNP60}, PPA1 (inorganic pyrophosphatase 1) [NCBI Gene 5464] {aka HEL-S-66p, IOPPP, PP, PP1, SID6-8061}, PPP2CA (protein phosphatase 2 catalytic subunit alpha) [NCBI Gene 5515] {aka HJS3, NEDLBA, PP2Ac, PP2CA, PP2Calpha, RP-C}, AKAP1 (A-kinase anchoring protein 1) [NCBI Gene 8165] {aka AKAP, AKAP121, AKAP149, AKAP84, D-AKAP1, PPP1R43}, SRSF3 (serine and arginine rich splicing factor 3) [NCBI Gene 6428] {aka SFRS3, SRp20}, AKT3 (AKT serine/threonine kinase 3) [NCBI Gene 10000] {aka MPPH, MPPH2, PKB-GAMMA, PKBG, PRKBG, RAC-PK-gamma}, TRA2B (transformer 2 beta homolog) [NCBI Gene 6434] {aka Htra2-beta, PPP1R156, RAMELN, SFRS10, SRFS10, TRA2-BETA}, DYRK4 (dual specificity tyrosine phosphorylation regulated kinase 4) [NCBI Gene 8798], CLK1 (CDC like kinase 1) [NCBI Gene 1195] {aka CLK, CLK/STY, STY}, MCL1 (MCL1 apoptosis regulator, BCL2 family member) [NCBI Gene 4170] {aka BCL2L3, EAT, MCL1-ES, MCL1L, MCL1S, Mcl-1}, SRSF9 (serine and arginine rich splicing factor 9) [NCBI Gene 8683] {aka SFRS9, SRp30c}, ALK (ALK receptor tyrosine kinase) [NCBI Gene 238] {aka ALK1, CD246, NBLST3}, SRPK1 (SRSF protein kinase 1) [NCBI Gene 6732] {aka SFRSK1}, DYRK3 (dual specificity tyrosine phosphorylation regulated kinase 3) [NCBI Gene 8444] {aka DYRK5, RED, REDK, hYAK3-2}, SRSF12 (serine and arginine rich splicing factor 12) [NCBI Gene 135295] {aka SFRS13B, SFRS19, SRrp35}, VEGFA (vascular endothelial growth factor A) [NCBI Gene 7422] {aka L-VEGF, MVCD1, VEGF, VPF}, HNRNPU (heterogeneous nuclear ribonucleoprotein U) [NCBI Gene 3192] {aka DEE54, EIEE54, GRIP120, HNRNPU-AS1, HNRPU, SAF-A}, SRPK3 (SRSF protein kinase 3) [NCBI Gene 26576] {aka MSSK-1, MSSK1, STK23, XLID114}, Cpd-3 [NCBI Gene 1165], SNRNP70 (small nuclear ribonucleoprotein U1 subunit 70) [NCBI Gene 6625] {aka RNPU1Z, RPU1, SNRP70, Snp1, U1-70K, U170K}, RNPS1 (RNA binding protein with serine rich domain 1) [NCBI Gene 10921] {aka E5.1}, NUCLEOLIN (nucleolin multifunctional protein) [NCBI Gene 4691] {aka C23, NCL, Nsr1}, TNS1 (tensin 1) [NCBI Gene 7145] {aka MST091, MST122, MST127, MSTP091, MSTP122, MSTP127}, MAPK14 (mitogen-activated protein kinase 14) [NCBI Gene 1432] {aka CSBP, CSBP1, CSBP2, CSPB1, EXIP, Mxi2}, MAPT (microtubule associated protein tau) [NCBI Gene 4137] {aka DDPAC, FTD1, FTDP-17, MAPTL, MSTD, MTBT1}, SRSF10 (serine and arginine rich splicing factor 10) [NCBI Gene 10772] {aka FUSIP1, FUSIP2, NSSR, PPP1R149, SFRS13, SFRS13A}, TRN-GTT2-7 (tRNA-Asn (anticodon GTT) 2-7) [NCBI Gene 7214] {aka TRN, TRN1}, PPP1CB (protein phosphatase 1 catalytic subunit beta) [NCBI Gene 5500] {aka HEL-S-80p, MP, NSLH2, PP-1B, PP1B, PP1Cbeta}, TNPO3 (transportin 3) [NCBI Gene 23534] {aka IPO12, LGMD1F, LGMDD2, MTR10A, TRN-SR, TRN-SR2}, SRSF4 (serine and arginine rich splicing factor 4) [NCBI Gene 6429] {aka SFRS4, SRP75}, CLK2 (CDC like kinase 2) [NCBI Gene 1196], ABCG2 (ATP binding cassette subfamily G member 2 (JR blood group)) [NCBI Gene 9429] {aka ABC15, ABCP, BCRP, BMDP, CD338, CDw338}, ATP7A (ATPase copper transporting alpha) [NCBI Gene 538] {aka DSMAX, HMNX, MK, MNK, SMAX3}, BRCA1 (BRCA1 DNA repair associated) [NCBI Gene 672] {aka BRCAI, BRCC1, BROVCA1, FANCS, IRIS, PNCA4}, PTPA (protein phosphatase 2 phosphatase activator) [NCBI Gene 5524] {aka PARK25, PP2A, PPP2R4, PR53}, BCL2L1 (BCL2 like 1) [NCBI Gene 598] {aka BCL-XL/S, BCL2L, BCLX, Bcl-X, PPP1R52}, SRSF5 (serine and arginine rich splicing factor 5) [NCBI Gene 6430] {aka HRS, SFRS5, SRP40}, SRSF1 (serine and arginine rich splicing factor 1) [NCBI Gene 6426] {aka ASF, NEDFBA, SF2, SF2p33, SFRS1, SRp30a}, CLK4 (CDC like kinase 4) [NCBI Gene 57396], YWHAQ (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein theta) [NCBI Gene 10971] {aka 14-3-3, 1C5, HS1}, BCL2 (BCL2 apoptosis regulator) [NCBI Gene 596] {aka Bcl-2, PPP1R50}, CTTNBP2 (cortactin binding protein 2) [NCBI Gene 83992] {aka C7orf8, CORTBP2, Orf4}, AR (androgen receptor) [NCBI Gene 367] {aka AIS, AR8, DHTR, HPCX3, HUMARA, HYSP1}, PRP4K (pre-mRNA processing factor kinase PRP4K) [NCBI Gene 8899] {aka PR4H, PRP4, PRP4H, PRPF4B, Prp4B, dJ1013A10.1}, FAS (Fas cell surface death receptor) [NCBI Gene 355] {aka ALPS1A, APO-1, APT1, CD95, FAS1, FASTM}, PPP1CC (protein phosphatase 1 catalytic subunit gamma) [NCBI Gene 5501] {aka PP-1G, PP1C, PPP1G} - **Diseases:** MDS (MESH:D009190), AML (MESH:D015470), metastasis (MESH:D009362), CCA (MESH:D018281), nausea (MESH:D009325), prostate cancer (MESH:D011471), hematologic malignancies (MESH:D019337), diarrhea (MESH:D003967), breast cancer (MESH:D001943), gastrointestinal tumor (MESH:D005770), TNBC (MESH:D064726), PDAC (MESH:D021441), colorectal and prostate cancer (MESH:D015179), NSCLC (MESH:D002289), diabetic macular oedema (MESH:D008269), vomiting (MESH:D014839), gliomas (MESH:D005910), pancreatic cancer (MESH:D010190), soft tissue sarcomas (MESH:D012509), cytotoxicity (MESH:D064420), gastric cancer (MESH:D013274), cancer (MESH:D009369), OC (MESH:D010051), fatigue (MESH:D005221), melanoma (MESH:D008545), tumorigenic (MESH:D002471), lung cancer (MESH:D008175) - **Chemicals:** ATP (MESH:D000255), ASTX727 (MESH:C000723076), benzothiazole (MESH:C005465), phosphates (MESH:D010710), gemcitabine (MESH:D000093542), SRPIN340 (MESH:C584061), platinum (MESH:D010984), TG003 (MESH:C487497), azacitidine (MESH:D001374), paclitaxel (MESH:D017239), T3 (MESH:D014284), ceramide (MESH:D002518), Zn (MESH:D015032), C6 pyridinium ceramide (MESH:C539200), C-DBS (-) - **Species:** Human alphaherpesvirus 1 (Herpes simplex virus type 1, no rank) [taxon 10298], Rattus norvegicus (brown rat, species) [taxon 10116], Homo sapiens (human, species) [taxon 9606] - **Cell lines:** U2OS — Homo sapiens (Human), Osteosarcoma, Cancer cell line (CVCL_0042), HeLa — Homo sapiens (Human), Human papillomavirus-related endocervical adenocarcinoma, Cancer cell line (CVCL_0030), COS7 — Chlorocebus aethiops (Green monkey), Transformed cell line (CVCL_0224) ## Figures 2 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12872631/full.md --- Source: https://tomesphere.com/paper/PMC12872631