Table 1.
Known roles of pseudokinases in disease
| Pseudokinase | Links to disease | Relevant pseudokinase domain mutations |
|---|---|---|
| ADCK3 | Mutations associated with cerebellar ataxia result in defects in coenzyme Q10 synthesis | Y514C |
| ANP-A (encoded byNPR1) | Polymorphisms associated with increased left ventricular mass index in essential hypertension; deletion in 5΄ flanking region associated with increased susceptibility to essential hypertension or left ventricular hypertrophy | NA |
| ANP-B (encoded byNPR2) | Loss-of-function mutations associated with acromesomelic dysplasia, Maroteaux type | Y708C, R776W |
| BUBR1 | Mutations associated with mosaic variegated aneuploidy; overexpression associated with tumour cell proliferation in gastric cancer and chromosomal instability in bladder cancer | R727C, R814H, I909T, L1012P |
| CASK | Mutations associated with X-linked mental retardation and FG syndrome | R28L, Y268H |
| DIA1R (encoded byCXORF36) | Mutations associated with X-linked mental retardation; deletions withinCXORF36associated with autism spectrum disorders | R128K |
| EPHA10 | Overexpression associated with prostate cancer and correlated with lymph node metastasis and stage progression in breast cancer | NA |
| EPHB6 | Downregulated in metastatic melanoma; expression level associated with tumour stage and survival in neuroblastoma and ovarian serous carcinoma; deletion mutation enhances cell migration and promotes a pro-metastatic phenotype in NSCLC cells | NA |
| FAM20A | Mutations associated with amelogenesis imperfecta prevent allosteric activation of FAM20C and exhibit reduced secretion | L173R, G331D, D403N |
| GCN2 | Promotes survival and proliferation in fibrosarcoma cells; genetic deletion improved synaptic plasticity and spatial memory in a mouse model of Alzheimer disease; promotes efficacy of yellow fever vaccine; mutations associated with pulmonary veno-occlusive disease | NA |
| HER3 (also known asERBB3) | Increased expression and persistent phosphorylation of HER3 contribute to drug resistance in cancer types such as breast and lung cancer; mutations promote oncogenesis and are found in several tumour types including breast, lung and gastrointestinal cancer; downregulated in dorsolateral prefrontal cortex in schizophrenia; overexpressed in Charcot–Marie–Tooth type1 disease | V695M, Q790R, S827I, E909G |
| HSER (encoded byGUCY2C) | Loss-of-function mutations linked to meconium ileum; activating mutation linked to familial diarrhoea syndrome; mRNA expression in CRC linked to time to recurrence and disease-free survival; suppresses intestinal tumour formation by inhibiting AKT | NA |
| ILK | Overexpression promotes cell migration and invasion in lung cancer and CRC | NA |
| IRAK2 | Hypofunctional mutations associated with reduced survival in CRC and reduced hepatitis C clearance | R214G, L392V |
| IRAK3 | Overexpression associated with deactivation of inflammatory response in monocytes upon exposure to tumour cells; mutations associated with early-onset, persistent asthma | L400V, R429Q |
| JAK1 JH2 | Mutations associated with acute leukaemias | A634D, H647Y, L653F, V658F, R724H, T782M, L783F |
| JAK2 JH2 | Mutations associated with myeloproliferative neoplasms, such as polycythaemia vera, and acute leukaemias | K607N, L611S, V617F, V717F |
| JAK3 JH2 | Inhibitory mutations associated with severe combined immunodeficiency; activating mutations associated with acute leukaemias | A572V, A573V, M576L, A593T, V715I, V722I |
| KSR1 | KSR1-null mice exhibit impaired tumorigenesis in RAS-driven cancers | NA |
| KSR2 | Mutations associated with obesity and insulin resistance; overexpression promotes anchorage-independent growth and transformation of oncogenic RAS-mutant cells | P662L, E667V, R684C, I801L, G816D, R818Q, R823H, D843N, S904L |
| MLKL | Required for necroptosis; overexpressed in autoimmune hepatitis | NA |
| NRBP1 | Downregulated in multiple cancers, including lung and colon adenocarcinomas; low expression levels in lung tumours correlate with reduced survival | NA |
| NRBP2 | Downregulated in hepatocellular carcinoma; high expression levels correlated with greater chemosensitivity and better prognosis | NA |
| PEAK1 (also known as SGK269) | Overexpressed in pancreatic cancer and a subset of breast cancers; required for KRAS-induced cell expansion in pancreatic cancer | NA |
| POMK (also known asSGK196) | Required for Lassa virus entry; loss-of-function mutations associated with Walker–Warburg syndrome, neuromuscular disorders and congenital muscular dystrophy | L137R, Q258R |
| Pragmin (also known as SGK223 or PRAG1) | Overexpressed in pancreatic cancer; required for SRC-mediated invasion in CRC | NA |
| PTK7 | Mutations lead to idiopathic scoliosis and neural tube defects; overexpression associated with lung and breast cancer; downregulated in metastatic melanoma and ovarian cancer | NA |
| PXK | Genetic variants that reduce B cell receptor internalization associated with systemic lupus erythematosus | NA |
| RETGC1 (encoded byGUCY2D) | Mutations associated with Leber congenital amaurosis and autosomal dominant cone–rod retinal dystrophy | F589S |
| RETGC2 (encoded byGUCY2F) | Mutations associated with pancreatic, lung and breast cancers | K672T |
| RNase L | Mediates innate immunity against viral and bacterial infections; overexpression observed in chronic fatigue syndrome; mutations associated with elevated risk of prostate cancer | R462Q |
| ROR1 | Overexpressed in several types of cancer, including CLL, ALL, gastric carcinoma and NSCLC | NA |
| ROR2 | Germline deletions associated with autosomal dominant brachydactyly type B; loss-of function mutations associated with autosomal recessive Robinow syndrome; overexpression associated with osteosarcoma and renal cell carcinoma | N620K |
| RPS6KL1 | Knockdown reduces cell survival of cervical carcinoma cells | NA |
| RYK | Inhibition of axon regeneration following spinal cord injury; overexpressed in epithelial ovarian cancer and associated with decreased overall survival | NA |
| S6KΔ1 (encoded byRPS6KC1) | Fusion of PX domain with AKT3 results in constitutively activated oncogenic fusion protein that promotes tumour growth of HR+breast cancer cells | NA |
| SCYL1 | Frameshift mutations associated with recessive form of spinocerebellar neurodegeneration and a hepatocerebellar neuropathy syndrome | NA |
| SCYL2 | Reduces release of HIV-1 by promoting Vpu dephosphorylation | NA |
| SCYL3 | Oncogenic fusion of TRKA kinase domain with SCYL3 pseudokinase domain and HEAT repeats is associated with CRC and promotes cell proliferation | NA |
| STK31 (also known asSGK396) | Overexpressed in CRC; inhibits differentiation; promotes cell migration and invasion | NA |
| STK40 (also known asSGK495) | Knockdown reduces cell viability in cervical carcinoma cells | NA |
| STRADα | Allosterically activates tumour suppressor LKB1; deletion of exons 9–13 associated with PMSE | NA |
| STRADβ | Allosterically activates tumour suppressor LKB1 | NA |
| STYK1 | Overexpressed in castration-resistant prostate cancer; low expression correlates with improved survival in hepatocellular carcinoma and decreased cell growth, migration and invasion | NA |
| TBCK | Mutations associated with infantile syndromic encephalopathy, intellectual disability and hypotonia | NA |
| Titin | Mutations associated with cardiomyopathy | NA |
| TRIB1 | Overexpression associated with AML and prostate cancer; gain-of-function mutation associated with acute megakaryocytic leukaemia; polymorphisms associated with altered lipid metabolism and cardiovascular disease | R107L |
| TRIB2 | Overexpressed in AML, lung cancer and liver cancer; promotes drug resistance in several cancer types, including melanoma and breast and renal cancers | NA |
| TRIB3 | Gain-of-function mutation associated with insulin resistance; overexpression associated with lung, colon and breast cancers; overexpression associated with Parkinson disease | Q84R |
| TRRAP | Necessary for MYC and E1A-mediated transformation | NA |
| TYK2 JH2 | Inhibitory mutations associated with autoimmune diseases, including systemic lupus erythematosus, Crohn’s disease and psoriasis; required for amyloid-β-induced neuronal apoptosis | I684S |
| ULK4 | Deletions of exons 21–34 and 33–34 in theULK4gene associated with schizophrenia | NA |
| VRK3 | Phosphorylation of VRK3 by CDK5 protects neuronal cells from oxidative stress-induced cell death by inhibiting ERK | NA |
A complete table including references can be found in the supplementary information. ALL, acute lymphocytic leukaemia; AML, acute myeloid leukaemia; ANP-A, atrial natriuretic peptide receptor type A; CDK5, cyclin-dependent kinase 5; CLL, chronic lymphocytic leukaemia; CML, chronic myeloid leukaemia; CRC, colorectal cancer; DIA1R, deleted in autism-related protein 1; EPHA10, pseudokinase ephrin receptor; HER, human epidermal growth factor receptor; HR, hormone receptor; HSER, heat-stable enterotoxin receptor; ILK, integrin-linked protein kinase; IRAK2, interleukin-1 receptor-associated kinase-like 2; JAK, Janus kinase; JH2, JAK homology 2; KSR, kinase suppressor of RAS; MLKL, mixed lineage kinase domain-like protein; NA, not applicable; NRBP1, nuclear receptor-binding protein 1; NSCLC, non-small-cell lung cancer; PMSE, polyhydramnios, megalencephaly, symptomatic epilepsy; POMK, protein O-mannose kinase; PTK7, protein tyrosine kinase 7; RETGC1, retinal guanylyl cyclase 1; RPS6KL1, ribosomal protein S6 kinase-like 1; RYK, receptor-like tyrosine kinase; SCYL1, SCY-like protein 1; STK, serine/threonine-protein kinase; STRADα, STE20-related adaptor-α; TRRAP, transformation/transcription domain-associated protein; TRIB1, Tribbles homologue 1.