From: The secret life of kinases: functions beyond catalysis
Kinase Group | Protein | Notes | Organism | References |
---|---|---|---|---|
Receptor Tyrosine Kinases | EGFR | Mitogen-activated protein kinase stimulation by a tyrosine kinase-negative epidermal growth factor receptor | CHO (Chinese hamster ovary) cells | [21] |
 |  | Tyrosine phosphorylation of mitogen-activated protein kinase in cells with tyrosine kinase-negative epidermal growth factor receptors | B82L cells (mouse) | [19] |
 |  | EGFR-ERBB2 oligomers activate ERK and Akt, independent of EGFR kinase activity | human | [24] |
 |  | Kinase-negative EGFR retains the capacity to stimulate DNA synthesis | CHO cell line (hamster) | [20] |
 |  | No kinase activity of EGFR is required for activation of c-fos expression | mouse | [23] |
 |  | Kinase-independent EGFR prevents autophagic cell death by maintaining intracellular glucose level through interaction and stabilization of the sodium/glucose cotransporter 1 (SGLT1). | human | [16] |
 |  | EGFR and EGFRvIII interact with PUMA to inhibit mitochondrial translocalization of PUMA and PUMA-mediated apoptosis independent of EGFR kinase activity. This function of EGFR/EGFRvIII leads to tumor drug resistance of glioblastoma. | human | [25] |
 | ApTrkl | Aplysia Trk-like receptor (ApTrkl), a Trk-like receptor in Aplysia sensory neurons, was shown to have two modes of receptor internalization: kinase activity-dependent internalization and serotonin-dependent, kinase activity-independent internalization | mouse | [213] |
 | Insulin Receptor | Unliganded insulin- and IGF-1 receptors exert a permissive effect on cell death | Mouse adipocytes | [214] |
 |  | Induces phosphorylation and activation of phosphatase PHLPP1, a negative regulator of Akt2 activity |  | [215] |
 | Insulin-Like Growth Factor I (IGF-1) Receptor | Mediates Erk1/2 phosphorylation in a tyrosine phosphorylation independent manner. | Smooth muscle cells | [34] |
 | EphA2 | Some of EphA2 functions in cell motility, invasion and bone formation are kinase-independent |  | [216] |
 | EphA4/SEK1 | Kinase-dependent and kinase-independent functions of EphA4 receptors in major axon tract formation in vivo | mouse | [217] |
 | EphA8 | Overexpression of EphA8 enhances cell attachment to fibronectin |  | [218] |
 | EphB/NUK | Kinase independent function of EphB receptors in retinal axon path finding to the optic disc from dorsal but not ventral retina | mouse | [219] |
 |  | Kinase-Independent Requirement of EphB2 Receptors in Hippocampal Synaptic Plasticity | mouse | [220] |
 |  | EphB2 regulates positioning of differentiated Paneth cells in small intestine independently of kinase activity | intestinal epithelium | [221] |
 | EphB3 | EphB3 is overexpressed in non-small-cell lung cancer and promotes tumor metastasis in a kinase-independent manner. | Lung | [222] |
 |  | Overexpression of wild type or kinase dead protein decreases Cdc42/Rac activity and reduces cell migration. |  | [223] |
 | EphA3 | In the absence of ephrin interaction, kinase-dead EphA3 recruits other Eph molecules for oligomerization | human | |
 | VAB-1 | VAB-1, a C. elegans Eph receptor, regulates embryonic development by kinase-dependent and -independent functions | C. elegans | |
 | c-kit | Complex formation with granulocyte macrophage colony-stimulating factor (GM-CSF) receptor. |  | [229] |
Non-receptor Tyrosine kinases | Src | Overexpresion of non-catalytic domains of Src alters focal adhesion properties | Â | [107] |
 |  | c-Src enhances the spreading of src-/- fibroblasts on fibronectin by a kinase-independent mechanism | mouse | [109] |
 |  | Activation of the Src-dependent adaptor protein pp130cas in fibroblasts in response to fibronectin binding does not require intrinsic Src kinase activity | mouse | [110] |
 |  | Kinase-deficient Src protects src-/- mice against osteopetrosis. | mouse | [112] |
 |  | Src mediates B cell antigen Receptor response |  | [230] |
 |  | Src mediates FAK phosphorylation at several tyrosine residues independently of its kinase activity | KM12C (Human colon cancer) | [111] |
 |  | Src regulates Jak2/Stat5 activation induced by prolactin in mammary tissue in a kinase-independent manner |  | [113] |
 | Brk | Brk (PTK6) promotes breast carcinoma cell proliferation |  | [231] |
 | FRK-1 | Fer-related kinase-1 (FRK-1) performs a kinase-independent function in differentiation and morphogenesis of the C. elegans epidermis during embryogenesis. | Caenorhabditis elegans | [232] |
 | Lck | Kinase-independent function of Lck in potentiating antigen-specific T cell activation | human | [114] |
 | Hck | The Src Family Kinase Hck Interacts with Bcr-Abl by a Kinase-independent Mechanism and Phosphorylates the Grb2-binding Site of Bcr-Abl | COS7 cells | [233] |
 | Lyn | Negative regulation of B cell Ag receptor (BCR) induced activation of Protein Kinase C (PKC) | Chicken B cells | [115] |
 |  | Lyn increases p53 levels and stimulates p53-mediated transcription by a kinase-independent mechanism |  | [234] |
 | c-Abl | Promotes p53 DNA binding |  | [235] |
 |  | Negatively regulates UV damaged DNA repair by recruiting CAL-4A ubiquitin ligase |  | [236] |
 |  | c-Abl promotes proteolytic destruction of damaged DNA binding proteins in a kinase-independent manner | mouse | [236] |
 |  | Abl proper subcellular localization is correlated with its kinase-independent activity | Drosophila | [237] |
 | FAK (Protein Tyrosine Kinase 2) | FAK initiates endothelial cell development during embryogenesis | Mouse endothelial cells | [124] |
 |  | FAK promotes cell survival by enhancing p53 degradation | Mouse fibroblasts and human cell lines | [126] |
 |  | Mediates JNK activation in a kinase-independent manner by recruiting paxillin to the plasma membrane |  | [118] |
 | Pyk2 (Protein Tyrosine Kinase 2 B) | Pyk2 facilitates cell growth and survival by limiting p53 levels | MEF and cell lines | [128] |
 | ACK (TNK2) | The scaffold function of ACK, rather than kinase activity, seems important in the context of cell growth control | human | [238] |
 | ACK2 | Overexpressed ACK2 inhibits kinase activity of FAK and cell growth independently of its kinase activity; however its ability to dissolve actin stress fibers and to disassemble focal complexes requires kinase activity | NIH3T3 cell line | [239] |
 | BMX | Bone Marrow Kinase (BMX) regulates inflammation in rheumatoid arthritis | mouse | [240] |
 | Itk | Itk mediates antigen receptor induced activation of transcription factor SRF (Serum Response Factor) independently of its kinase activity | DT40 chicken B cells | [241] |
 |  | Itk regulates Vav localization and T cell Receptor-induced actin polarization independently of its kinase activity. | T cells | [242] |
 | Zap-70 | Whereas the kinase activity of Zap-70 is required for signal transduction downstream to the T cell antigen receptor (TCR), this protein has kinase-independent functions in activating small G protein Rap1, required for integrin-mediated adhesion. | T cells | [243] |
TKL | TβRI | TGFβ receptor recruits and activates TAK1 via interaction with TRAF6 | human | [244] |
 | Raf-1 | Raf-1 binds to and inhibits ROK-alpha kinase activity | MEF | [66] |
 |  | Raf-1 plays an essential, kinase-independent function as a spatial regulator of Rho downstream signaling during migration. | MEF | [65] |
 |  | Raf-1 sets the threshold of Fas sensitivity by modulating ROK-α signaling | MEF | [64] |
 |  | Raf-1:ROK-alpha complex linked to STAT3/Myc activation is crucial for cell fate decisions in Ras-induced tumorigenesis. | mouse | [67] |
 |  | Raf-1 binds and inhibits the pro-apoptotic kinase MST2 | human and mouse cell lines | |
 |  | Raf-1 binds and inhibits the pro-apoptotic kinase ASK1 | mouse | [246] |
 |  | Cardiac-specific disruption of the Raf-1 gene induces cardiac dysfunction and apoptosis | mouse | [75] |
 |  | Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK-ERK independent mechanism | human | [74] |
 |  | MEK kinase activity of Raf-1 is not essential for function and normal mouse development. Raf-1 plays a role in preventing apoptosis. | mouse | |
 | A-Raf | A-Raf binds and inhibits the pro-apoptotic kinase MST2 | human | |
 | Raf-1/B-Raf | Regulation and role of Raf-1/B-Raf heterodimerization | human | |
 |  | Mixed-lineage kinase 3 (MLK3) regulates B-Raf through maintenance of the B-Raf/Raf-1 complex and inhibition by the NF2 tumor suppressor protein | human | [55] |
 |  | Diacylglycerol Kinase η Augments C-Raf Activity and B-Raf/C-Raf Heterodimerization | human | [56] |
 | PKK | Protein kinase C-associated kinase (PKK, also known as RIP4/DIK) lacking kinase activity can induce partial activation of NFκB |  | [247] |
CMGC | ERK | ERK (Extracellular signal-regulated kinase) acts as a transcriptional repressor for interferon gamma-induced genes. | human | [89] |
 |  | Catalytic Activation of the Phosphatase MKP-3 by ERK2 Mitogen-Activated Protein Kinase | human | [86] |
 |  | ERK Activates Topoisomerase IIalpha through a Mechanism Independent of Phosphorylation | mouse, human | [84] |
 |  | ERK1/2 MAP kinases promote cell cycle entry by rapid, kinase-independent disruption of retinoblastoma-lamin A complexes. | human | [91] |
 |  | PARP-1 usually gets activated by DNA strand breaks and is required for DNA repair. ERK2 activates PARP-1 independently of DNA strand breaks | rat | [85] |
 | ERK3 | ERK3, an atypical member of the MAPK family, interacts with MAPK-activated protein kinase 5 (MK5 or PRAK) independent of ERK3 enzymatic activity. Erk3 regulates MK5 cellular localization and activation thus being involved in embryonic development. | mouse | [248] |
 | ERK5/Mpk1 | Erk5, a member of the MAPK family, associates with the Paf1 complex thereby blocking Sen1-mediated premature transcription termination. | yeast, human | [249] |
 | Erk8 | Erk8 negatively regulates transcriptional co-activation of androgen receptor and GRalpha by Hic-5 in a kinase-independent manner |  | [250] |
 | p38 MAPK | p38 inhibits cell cycle progression in a kinase-independent fashion, whereas promotes G2/M checkpoint in a kinase-dependent manner | Several human and murine cell lines | [98] |
 |  | p38 blocks transcription in proliferating cells by sequestering transcription co-activator Mirk/Dyrk1B | NIH3T3/human cell lines | [99] |
 | Cdc2 | Cdc2 blocks cell cycle in S phase via inhibition of E2F | Drosophila | [251] |
 | Cdk1/cdc28 | Cdk1/cdc28 recruits proteosomes to coding region to maintain transcriptional activity | yeast | [252] |
 | Cdk5 | Cdk5 is a cell cycle suppressor in normal post-mitotic neurons | Mouse primary neurons | [253] |
CK1 | Casein Kinase 1ε | Casein Kinase 1ε regulates Fz/planar cell polarity (PCP) pathway in Drosophila development in a kinase-independent manner, whereas Wnt-Frizzled (Fz)/beta-catenin pathway requires its kinase activity | Drosophila | [254] |
 | VRK-3 | Vaccinia-related kinase 3 (VRK-3), a member of the VRK family, suppresses ERK activity through direct binding to the MAPK phosphatase Vaccinia H1-related (VHR). VHR is known to dephosphorylate and inactivate ERK in the nucleus. |  | [255] |
CAMK | AMPK | AMP-activated protein kinase α (AMPKα) acts as transcriptional co-activator of PPAR under ATP deprivation | Rat hepatocytes | [256] |
 | MARK2 | MARK2 regulates neuronal morphology independently of kinase activity | Neuronal cells | [257] |
 | DAPK | Death-associated protein kinase (DAPK) increases glycolytic rate through binding and activation of pyruvate kinase |  | [258] |
STE | MEK5 | A constitutively active form of MEK5 is able to inhibit SUMOylation of the atypical MAPK ERK5 independent of kinase activity, but dependent on MEK5-ERK5 association | mouse | [259] |
 | MEKK1 | The PHD domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination and degradation of ERK1/2 | human | [260] |
 | PAK1 (p21-activated kinase1) | Recruits Akt to the plasma membrane and facilitates Akt1 and PDK1 interaction | Cell lines including Cos and NIH 3T3 | [136] |
 |  | Overexpressed PAK1 induced lamellipodia formation and membrane ruffling independently of its catalytic activity | REF52 cell line | [133] |
 |  | PAK1 targeted to the plasma membrane promotes cell differentiation in the PC12 model independently of its kinase activity | PC12 | [132] |
 |  | Overexpressed PAK promotes F-actin accumulation in a kinase independent manner, whereas its effect on cell shape is kinase-dependent | Swiss 3T3 | [134] |
 |  | PAK1 promotes formation of multiprotein complex in focal adhesions that consists of PAK-PIX-PKL-Paxillin. Conformational change, but not kinase activity of PAK1 is required for complex formation | CHO cells | [135] |
 |  | PAK1 induces activation of exchange factor, PIX, upon binding Gβγ. This leads to Cdc42 activation and subsequently PAK1 kinase activation. | Myeloid cells | [137] |
 | PAK2 | PAK2 controls spindle orientation independently of its kinase activity | HeLa cells | [139] |
 | PAK4 | PAK4 mediates TNFα-induced cell survival by promoting recruitment of TRADD to TNFα receptor | HeLa cells | [149] |
 |  | PAK4 promotes cell survival by inhibiting caspase activation | Human (HeLa cells) and mouse (NIH3T3) | |
 | ASK1 (MAP3K5) | ASK1 inhibits NF-κB-induced cell survival by perturbing TRAF6-TAK1 interaction | HEK293 | [80] |
 |  | ASK1 induces a Daxx-dependent caspase-independent cell death |  | [78] |
 | MST1 | MST1 serine-threonine kinase, a component of the RASSF1-LATS tumor suppressor network, binds androgen receptor (AR), but the kinase activity of MST1 is not involved in inhibition of AR. | human, mouse | [262] |
AGC | PDK1 | Interacts with Ral-GDS and induces its GEF activity of in PI3 kinase dependent manner | Â | [182] |
 |  | Forms a multiprotein complex, required for NFkB activation upon TCR activation in T cells |  | [181] |
 | Gprk2/GRK2 | G protein-coupled receptor kinase 2 (Gprk2) promotes high-level Hedgehog signaling by regulating the active state of Smo through kinase-dependent and kinase-independent mechanisms in Drosophila | Drosophila | [263] |
 |  | Kinase activity-independent regulation of the cyclin pathway by GRK2 is essential for zebrafish early development. | Zebrafish | [264] |
 |  | Interaction assays of the neurokinin-1 (NK-1) receptor with G-protein coupled receptor kinases (GRKs) reveal that GRK5 interaction with the receptor was dependent on intact kinase-activity, whereas the high affinity phase of GRK2 interaction was independent of kinase activity. |  | [265] |
 | Gprk2 | G Protein-coupled Receptor Kinase 2 (Gprk2) has kinase-independent functions during Histamine H2 receptor desensitization |  | [266] |
 | MSK2 | Mitogen- and stress-activated protein kinase 2 (MSK2), a member of the ribosomal S6 kinase (RSK) family, functions as an adaptor in mediating activation of PKR (double-stranded RNA (dsRNA)-activated protein kinase) independent of its catalytic activity. | human | [267] |
Atypical | mTOR (FRAP) | Differentiation of myoblasts can be rescued by Rapamycin-insensitive or Rapamycin-insensitive kinase-dead mTOR | mouse | [192] |
 |  | Dystrophin expression muscle cells | mouse | [195] |
 |  | Negative regulation of microRNA-125b expression in skeletal muscles during differentiation and muscle regeneration | Mouse | [268] |
 | Rad3 (ATR) | Rad3 (ATR)-Rad26 (ATRIP) complex can recruit Tel1(ATM) to telomeres independently of Rad3(ATR) kinase activity. | Fission yeast (Schizosaccharomyces pombe) | [269] |
 | Tel1 | ATM-related protein, Tel1, regulates telomere maintenance in yeast. | Budding yeast (Saccharomyces cerevisiae) | [270] |
 | H11 | H11 has two functions in cardiac cells: At low doses, it induces hypertrophy through kinase-independent activation of Akt, whereas at high doses H11 causes apoptosis through protein kinase-dependent mechanisms by inhibition of CK2. | mouse | [271] |
Other kinases | Wnk | With-no-lysine (K) kinases (Wnk) regulate ion transport via both catalytic and non-catalytic mechanisms. While regulation of cation-chloride-coupled cotransporters, Na+-K+-2Cl(-) cotransporter (NKCC) 1, and NKCC2 by WNKs requires kinase activity, intersectin-mediated endocytosis of ROMK1 is independent of Wnk kinase activity. | Â | [272] |
 |  | Wnk1 mediates activation of SGK1 downstream to the Insulin-like growth factor 1. |  | [200] |
 | WNK2 | Tumor suppressor as indicated by preventing colony formation in glioma cells |  | [273] |
 | ILK | ILK interaction with α-parvin but not its kinase activity is required for embryonic development | Mouse | [274] |
 |  | ILK links the cytoskeleton and the plasma membrane at sites of integrin-mediated adhesion. | Dosphila/C. Elegans | |
 |  | ILK regulates actin reorganization in chondrocytes and modulates chondrocyte growth independently of phosphorylation of Pkb/Akt and GSK3-beta. | mouse | [277] |
 |  | ILK regulates cell polarization, adhesion and actin accumulation at the integrin-adhesion sites | mouse | [278] |
 |  | ILK controls epidermis and hair follicle morphogenesis by modulating integrin-mediated adhesion, actin reorganization, and plasma membrane dynamics in keratinocytes | mouse | [279] |
 | IKKα | IKKα controls epidermis formation via regulation of keratinocyte differentiation in a NF-κB-independent fashion | mouse | [280] |
 | IKKβ | Regulates vascular permeability and migration of endothelial cells by regulating Akt activation. | Endothelial cells | [281] |
 | Aurora A/AIR-1 | Aurora (AIR-1) stabilizes spindle microtubules independently of its kinase activity, however kinase activity is required for centrosome regulation | C. elegans | [282] |
 | TLK-1 | Tousled-like kinase (TLK-1) mediates activation of Aurora B kinases independently of kinase activity thus regulating cell division | Budding yeast (Saccharomyces cerevisiae) | [283] |
 | Fa2p | Fa2p, a member of the NIMA-family of kinases (Neks), regulates cell cycle by associating with the proximal end of centrioles. While this cell cycle function of Fa2p is kinase independent, its function of coordinating of cilia is kinase dependent. | Chlamydomonas, Kidney cells | [284] |
 | Nek2B | Nek2B, NIMA-related protein kinase, promotes assembly of a functional zygotic centrosome independently of its kinase activity | Xenopus laevis | [285] |
 | Apg1/Atg1 | In autophagic cells, Apg1 (Ulk-1 in human) kinase activity is required only for Cvt trafficking of aminopeptidase I but not for import via autophagy. | yeast | [286] |
Lipid kinases | p110β | The catalytic activity of p110β is dispensable for embryonic development | Mouse | [158] |
 |  | DNA replication during the S phase |  | [162] |
 |  | Mediates double-strand DNA break repair via catalytic and non-catalytic mechanisms | MEF and NIH 3T3 | [161] |
 |  | Endocytosis and oncogenic transformation as indicated by transferin uptake and foci formation, respectively. | MEF | [159] |
 | p110γ | p110γ regulates integrin activation in platelets and thrombus formation in a kinase-independent manner; p110β contributes to the same process by PIP3 production | Mouse | [287] |
 |  | Negatively regulates cardiac contractility by mediating phosphodiesterase 3B activation and thus leading to cAMP destruction | Heart (mouse) | [174] |
 |  | p110gamma binds phosphodiesterase 3B, whereas the regulatory subunit of PI3K, p87 binds Protein Kinase A (PKA). PKA, activated by cAMP phosphorylates phosphodiesterase 3B and therefore leads to negative regulation of cAMP levels in cardiomyocytes. |  | [176] |
 |  | Protective role during myocardial ischemia and reperfusion injury | Endothelial progenitor cells (mouse) | [169] |
 |  | Reparative neovascularisation after unilateral limb ischemia | mouse | [168] |
 | p85 | Positivey regulates JNK activation in a response to insulin stimulation | brown adipose cells | [288] |
 |  | GTPase activity towards Rab4 and Rab5 small G proteins, as part of negative PDGF regulation. Prevents cell transformation |  | [289] |
 |  | p85 controls mammalian cytokinesis by regulating Cdc42 activation |  | [290] |
 | IP3K-A | IP3K-A (Ins(1,4,5)P(3) 3-kinase-A) regulates cytoskeletal organization in a kinase-independent manner | Lung epithelial cells (H1299) | [291] |