ABC1 kinases are family of aarF domain-containing protein kinases which belong to atypical kinase group. Five members have been identified in human genome, known as ADCK1-ADCK5. ABC1 kinases contain the conserved protein kinase motifs which is responsible for the ATP binding and phosphotransfer reaction. However, as the overall sequence is distinct with ePK domain and lack of several usual kinase motifs, they are classified into "Atypical" kinase group (1).

Reference
1. Lagier-Tourenne, C., Tazir, M., Lopez, L.C., Quinzii, C.M., Assoum, M., Drouot, N., Busso, C., Makri, S., Ali-Pacha, L., Benhassine, T. et al. (2008) ADCK3, an ancestral kinase, is mutated in a form of recessive ataxia associated with coenzyme Q10 deficiency. Am J Hum Genet, 82, 661-672. PMID: 18319074

    Alpha kinases belong to atypical kinase group and lack significant sequence similarity to ePK (1). Six members have been identified in mammals, including elongation factor 2 kinase, Dictyostelium myosin heavy chain kinases and other protein kinases. eEF-2 is involve in regulation of the global rate of protein synthesis and MHCK A is essential in regualtion of myosin assembly and disassembly. Although no detectable sequence identity between ePK and Alpha kinases has been found, the structure, sequence motifs and key amino acid residue position are very similar. The differences may impact on substrate recognition (2).

Reference
1. Manning, G., Whyte, D.B., Martinez, R., Hunter, T. and Sudarsanam, S. (2002) The protein kinase complement of the human genome. Science, 298, 1912-1934. PMID: 12471243
2. Drennan, D. and Ryazanov, A.G. (2004) Alpha-kinases: analysis of the family and comparison with conventional protein kinases. Prog Biophys Mol Biol, 85, 1-32. PMID: 15050379

    BCR (breakpoint cluster region) kinases belong to atypical kinase group, and the kinase domains share no significant sequence with ePK. BCR can be mapped on chromosome 22 in human genome and can form a fusion gene with Abl from chromosome 9. This reciprocal translocation event will lead to an aberrant chromosome Ph formation which is responsible for the chronic myeloid leukaemia (CML). The normal BCR also possess the kinase activity and can auto- and trans-phosphorylate serine, threonine and tyrosine residues. Sequence analysis shows that BCR contains a protein kinase domain in N-terminal, followed by a SH2 domain and a GEF domain, a GTPase activity (GAP) domain is in C-terminal. BCR has been found involved in CML and many important signaling pathways. The identified substrates include 14-3-3 Tau, MLLT4 and PPARg (1).

Reference
1. Clokie, S.J., Cheung, K.Y., Mackie, S., Marquez, R., Peden, A.H. and Aitken, A. (2005) BCR kinase phosphorylates 14-3-3 Tau on residue 233. FEBS J, 272, 3767-3776. PMID: 16045749

    BRD (Bromodomain) kinases belong to atypical kinase group and the sequences of BRD kinase share no significant similarity to ePK. BRD proteins contain two bromodomain domains, they are associated with chromatin. Four members have been found in mammals (BRD2, BRD3, BRD4 and BRDT). Proteins with single bromodomain are not clearly orthologus to BRD, but may have related functions (1). Human BRD2 was first identified in Hela extracts and found to contain an autophosphorylation activity, but the activity can only be observed when purified recombinant protein was first incubated with Hela cell extract and repurified (2). BRD4 also contains the autophosphorylation and transphosphorylation activity. Bromodomain deletion will lead to the loss of activity (1).

Reference
1. Wikinome annotation: Kinase Family BRD
2. Manning, G., Whyte, D.B., Martinez, R., Hunter, T. and Sudarsanam, S. (2002) The protein kinase complement of the human genome. Science, 298, 1912-1934. PMID: 12471243

    FAST (Fas-activated Serine/Threonine) kinase can catalyze the phosphate group transfer from ATP to Fas-activated Serine/Threonine protein. TIA1 is substrate of FAST kinase, and the phosphorylation will lead to inclusion of FAS exon6, which will produce an mRNA encoding a pro-apoptotic form of teh receptor (1). Since the overall sequence of FAST shares no similarity with ePK, FAST is classified into "Atypical Protein Kinase" group (2).

Reference
1. UniProt Annotation: FASTK_HUMAN
2. Manning, G., Whyte, D.B., Martinez, R., Hunter, T. and Sudarsanam, S. (2002) The protein kinase complement of the human genome. Science, 298, 1912-1934. PMID: 12471243

    G11 family contains a single human gene and belongs to atypical kinase group (1). G11 has been shown to posses the ser/thr kinase activity against alpha casein and histone, but the activity can only be observed in immunoprecipitates from Sf21 insect cells and primate COS cells. G11 contains the ATP-binding ability and the kinase activity remains to be more understood. It is suggested that another kinase binds G11 and perform its kinase activity (2).

Reference
1. Manning, G., Whyte, D.B., Martinez, R., Hunter, T. and Sudarsanam, S. (2002) The protein kinase complement of the human genome. Science, 298, 1912-1934. PMID: 12471243
2. Wikinome annotation: Kinase Family G11

     HK catalyzes the phosphorylation of glucose to produce glucose 6-phosphate, using ATP as a phosphate donor. HK1 can also phosphorylate purified histone H2A in vitro phosphorylation assays. In addition, HK-PII, an isoenzyme from Saccharomyces cerevisiae, can autophosphorylate itself (1).

Reference
1. Lu Z, Hunter T. (2018) Metabolic Kinases Moonlighting as Protein Kinases. Trends Biochem Sci, 43(4), 301-310. PMID: 29463470

     KHK, known as fructokinase, the first rate-limiting metabolic enzyme, catalyzes the conversion of fructose and ATP to fructose 1-phosphate (F1P) and ADP, respectively. KHK-A can also function as a protein kinase and directly phosphorylate PRPS1 at Thr225 (1).

Reference
1. Lu Z, Hunter T. (2018) Metabolic Kinases Moonlighting as Protein Kinases. Trends Biochem Sci, 43(4), 301-310. PMID: 29463470

    PDHK (Pyruvate Dehydrogenase Kinases) belong to atypical kinase group (1). PDHKs are related to histidine kinases, but the phosphorylation site is serine rather than histidine or aspartate. The structure analysis shows that PDHKs contain an N-terminal BCDHK_Adom3 domain and a C-terminal histidine kinase-like domain. The only substrate of PDHK is the E1 subunits of Pyruvate Dehydrogenase (PDH) and the phosphorylation occurs on three serine residues S230, S293 and S300 in human. PDHK is associated with diseases and can be a target for diabetes therapies (2).

Reference
1. Manning, G., Whyte, D.B., Martinez, R., Hunter, T. and Sudarsanam, S. (2002) The protein kinase complement of the human genome. Science, 298, 1912-1934. PMID: 12471243
2. Wikinome annotation: Kinase Family PDHK

    PGK1 is the first ATP-generating enzyme in this pathway and is highly expressed in many types of cancer (1). In the mitochondria, PGK1, acting as a protein kinase, interacts with and directly phosphorylates pyruvate dehydrogenase kinase isozyme 1 (PDHK1) at Thr338 using ATP as a phosphate donor. In addition, acetylated PGK1 interacts with Beclin1 and phosphorylates it at Ser30 to induce autophagy (2).

Reference
1. Lu Z, Hunter T. (2018) Metabolic Kinases Moonlighting as Protein Kinases. Trends Biochem Sci, 43(4), 301-310. PMID: 29463470
2. Qian X, Li X, Cai Q, Zhang C, Yu Q, Jiang Y, Lee JH, Hawke D, Wang Y, Xia Y, Zheng Y, Jiang BH, Liu DX, Jiang T, Lu Z. (2017) Phosphoglycerate Kinase 1 Phosphorylates Beclin1 to Induce Autophagy. Mol Cell, 2, 65(5),917-931. PMID: 28238651

    Phosphatidylinositol-3 kinase-related kinases (PIKKs) belong to atypical protein kinase group, which share little similarity of kinase catalytic domain. PIKKs family contains six members which are involved in responding to various stresses, including DNA damage, blocks in DNA replication, availability of nutrients and errors in mRNA splicing. The protein kinase domain of PIKKS, located in C-terminus, is always flanked by two conserved domain, known as FAT and FATC domain, which may interact and participate in kinase regulation (1). ATM, one of family member, is involved in responding to a specific type of DNA damage, such as DNA double strand breaks, and controls the cell-cycle progression by phosphorylates multiple substrates including p53 and Chk2. In addition, ATM also locates in cytoplasmic especially in neuronal or neuron-like cells (2). Ataxia telangiectasia and Rad3-related protein (ATR) acts as a DNA damage sensor. Activated by DNA lesions including base adducts, crosslinks, DSBs, and compounds that directly promote replication stress such as hydroxyurea and aphidicolin and phosphorylates multiple substrates to control the DNA replication and mitosis (3). mTOR is a serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals. mTOR is regulated by dynamic changes in cellular localization (3). Transformation/transcription domain-associated protein (TRRAP) is also structurally related to the PIKK family. TRRAP proteins (Tra1 in budding yeast) are common components of many histone acetyltransferase (HAT) complexes, and mediate a variety of cellular processes by recruiting HAT complexes to chromatin (4).

Reference
1. Lempiainen, H. and Halazonetis, T.D. (2009) Emerging common themes in regulation of PIKKs and PI3Ks. EMBO J, 28, 3067-3073. PMID: 19779456
2. Yang, D.Q., Halaby, M.J., Li, Y., Hibma, J.C. and Burn, P. (2011) Cytoplasmic ATM protein kinase: an emerging therapeutic target for diabetes, cancer and neuronal degeneration. Drug Discov Today, 16, 332-338. PMID: 21315178
3. Lovejoy, C.A. and Cortez, D. (2009) Common mechanisms of PIKK regulation. DNA Repair (Amst), 8, 1004-1008. PMID: 19464237
4. Kanoh, J. and Yanagida, M. (2007) Tel2: a common partner of PIK-related kinases and a link between DNA checkpoint and nutritional response? Genes Cells, 12, 1301-1304. PMID: 18076567

    Pyruvate kinase regulates the final rate-limiting step of glycolysis, which catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP), yielding one molecule of pyruvate and one molecule of adenosine triphosphate (ATP). PKM2 binds to the spindle checkpoint protein Bub3 during mitosis and phosphorylates Bub3 at Tyr207 (1). Using PEP as a phosphate donor, nuclear PKM2 can also phosphorylate histone H3 at Thr11 in nucleosomes associated with gene promoter regions (2). Notably, PKM2 binds directly and selectively to tyrosine (Tyr, Y)-phosphorylated peptides, and expression of the phosphotyrosine-binding form of PKM2 is required for the rapid growth of cancer cells (3).

Reference
1. Yang W, Xia Y, Hawke D, Li X, Liang J, Xing D, Aldape K, Hunter T, Yung WKA, Lu Z. (2014) PKM2 Phosphorylates Histone H3 and Promotes Gene Transcription and Tumorigenesis. Cell, 158(5), 1210. PMID: 28917293
2. Lu Z, Hunter T. (2018) Metabolic Kinases Moonlighting as Protein Kinases. Trends Biochem Sci, 43(4), 301-310. PMID: 29463470
3. Kaneko T, Joshi R, Li SS. (2012) Phosphotyrosine recognition domains: the typical, the atypical and the versatile. Cell Commun Signal, 10(1), 32. PMID: 23134684

    RIO family belongs to atypical protein kinase group, which shares little similarity of high kinase domain with ePK. RIO family is present in organisms varying from archaea to humans. All these organisms contain at least two RIO proteins, Rio1 and Rio2, but a third Rio3 group is present in multicellular eukaryotes. Rio1 and Rio2 possess kinase activity which has been demonstrated shown to be essential in S. cerevisiae and required for proper cell cycle progression and chromosome maintenance (1).

Reference
1. LaRonde-LeBlanc, N. and Wlodawer, A. (2005) The RIO kinases: an atypical protein kinase family required for ribosome biogenesis and cell cycle progression. Biochim Biophys Acta, 1754, 14-24. PMID: 16182620

    TAF1, transcription initiation factor TFIID subunit 1, is a protein encoding by TAF1 gene and belongs to atypical protein kinase group (1). TAF1 is involved in basal transcription and regulation of promoter recognition and help GTFs form complex assembly and start the transcription. TAF1 contains two protein kinase domains located at N-terminal and C-terminal, and TAF1 also possesses the acetyltransferase and ubiquitin-activating/conjugating activity (2).

>Reference
1. Manning, G., Whyte, D.B., Martinez, R., Hunter, T. and Sudarsanam, S. (2002) The protein kinase complement of the human genome. Science, 298, 1912-1934. PMID: 12471243
2. Wikipedia annotation: TAF1

    TIF1, Transcriptional Intermediary Factor 1, contains three members in human genome, TIF1a, TIF1b and TIF1g, and belong to atypical protein kinase group (1). The autophosphorylation activity of TIF1a has been detected in immunopurified, bacculovirus-produced protein. TIFs participate in transcriptional machinery and may mediate the phosphorylation of several TATA-associated factors. Bromodomains are also found in TIFs, which are present in BRD kinase family, which suggest that bromodomain is associated with kinase activity (2).

Reference
1. Manning, G., Whyte, D.B., Martinez, R., Hunter, T. and Sudarsanam, S. (2002) The protein kinase complement of the human genome. Science, 298, 1912-1934. PMID: 12471243
2. Wikipedia annotation: TIF1.