Aurora kinases are classified into "Other" group. Three members have been identified in human genome, AurA, AurB and AurC. Sequence analysis show that Aur kinases contain a conserved kinase catalytic domain flanked by N-terminal and C-terminal regulatory sequence. AurA gene is located within the chromosome locus 20q13, which is a frequently detected in human breast tumors, and AurA is essential for the proper progression through mitosis. AurB is a chromosome passenger involved in cytokinesis and chromosome architecture and AurC plays a role in spermatogenesis at the time when cells assemble the two meiotic spindles, AurC can also cooperates with AurB to regulate mitotic chromosome dynamics. AurA has been reported to be a good marker of tumor progression and prognosis, which can be applied on disease diagnosis and treatment (1).

Reference
1. Bolanos-Garcia, V.M. (2005) Aurora kinases. Int J Biochem Cell Biol, 37, 1572-1577. PMID: 15896667

    BUB family contains two serin/threonine protein kinases: BUB1A (BUB1) and BUB1B. BUB kinases comprise a conserved N-terminal region, followed by a non-conserved region and a kinase catalytic domain in C-terminal. N-terminal region is responsible for binding to mitotic kinetochore protein blinkin. Human BUB1A accumulates during G1 and S phase in cell cycle, achieve the maximum in G2/M and drops after mitosis. The function of BUB1A is distinct during cell cycle, mainly in the SAC and chromosome alignment during metaphase. BUB1A can bind to Kinetochores and be involved in establishment of the mitotic spindle checkpoints and chromosome congression. Function loss or abnormal expression of BUB1A have been identified in a lot of human tumors, including colon, breast cancer, gastric and melanoma, which is correlated with the understanding that many cancers is associated with disturbed mitotic checkpoints (1).

Reference
1. Wikipdia Annotation:   BUB1

    BUD32 belong to "Other" group. One member, PRPK, have been identified in human genome. PRPK is also known as p53-related protein kinase. PRPK was first cloned form interleukin-2-activated cytotoxic T-cell subtraction library, and the expression could also be observed in some human epithelial tumor cell lines, and the testes. PRPK seems to be a homologue of a kinase from yeast, YGR262c, which is a growth-related ser/thr protein kinase. However, the functions of two kinases are not identical. Studies show that PRPK can bind to p53 and mediate the phosphorylation of p53 at ser-15. So PRPK might involve in cell cycle and apoptosis (1).

Reference
1. Abe, Y., Matsumoto, S., Wei, S., Nezu, K., Miyoshi, A., Kito, K., Ueda, N., Shigemoto, K., Hitsumoto, Y., Nikawa, J. et al. (2001) Cloning and characterization of a p53-related protein kinase expressed in interleukin-2-activated cytotoxic T-cells, epithelial tumor cell lines, and the testes. J Biol Chem, 276, 44003-44011. PMID: 11546806

    CAMKKs (Ca2+/calmodulin-dependent protein kinase kinases) are classified into "Other" group. Two distinct genes encoding CAMKKs are indentified in human genome, CAMKKα and CaMKKβ. The two protein kinases sequences are 69% identical. CAMKKs are composed of a N-terminal protein kinase catalytic domain and a regulatory domain at its C-terminal region, which consists of the CaM-binding site overlapped with the autoinhibitory domain. The two members localized in different regions of the brains, CAMKKα is widely distributed in neurons, except in the cerebellar cortex, and CaMKKβ can be found in some neuronal populations, such as the cerebellar granule cells. CAMKKs are characterted by its important in CAMK cascade pathway via acting as an upstream activator of CAMKs such as CaMK I and CaMK IV, which is analogous to the MAPK cascade pathway. In addition, rat CAMKKα has been found to phosphorylate and activate protein kinase B, and in turn regulate the cell apoptosis (1).

Reference
1. Hsu, L.S., Chen, G.D., Lee, L.S., Chi, C.W., Cheng, J.F. and Chen, J.Y. (2001) Human Ca2+/calmodulin-dependent protein kinase kinase beta gene encodes multiple isoforms that display distinct kinase activity. J Biol Chem, 276, 31113-31123. PMID: 11395482

    CDC7s (Cell division cycle 7 kinases) are classified into Others family. One member, CDC7, was first indentified in budding yeast genome and human homolog was identified later. The kinase catalytic domain is conserved among human, yeast and fission yeast by comparison of primary sequence. The studies show that human CDC7 is localized in the nucleus and posses a protein kinase activity. The expression level is constant while the kinase activity is unstable with the maximum in S phase of the cell cycle. CDC7 functions as a nuclear protein ser/thr kinase required at G1/S phase transition in the mitotic cell cycle in yeast. The CDC7 can bind to the regulatory subunit Dbf4p which is required for the initiation of DNA replication (1). In mammals, the major target of CDC7 is MCM complex which may have the similar functions with Dbf4p (2).

Reference
1. Jiang, W. and Hunter, T. (1997) Identification and characterization of a human protein kinase related to budding yeast Cdc7p. Proc Natl Acad Sci U S A, 94, 14320-14325. PMID: 9405610
2. Montagnoli, A., Moll, J. and Colotta, F. (2010) Targeting cell division cycle 7 kinase: a new approach for cancer therapy. Clin Cancer Res, 16, 4503-4508. PMID: 20647475

    Haspin (haploid cell-specific protein kinase) family contains one member in human genome. Haspin was first found in male germ cells of mice and Haspin homologues have been identified in a range of eukaryotic organisms. These homologues contain a divergent kinase catalytic domain which is different with classical ePKs. Experiment shows that expression of Haspin is high in testis in human with low levels in multiple somatic tissues. Haspin is a nuclear protein in interphase nuclei and in round spermatids and is associated with chromosomes in mitosis. Studies show that Haspin depletion can cause a defect in chromosome congression and a delay in exit from mitosis. In addition, Haspin-depleted cells can lead to the chromosome alignment defects and overexpression can prevent the normal dissociation of cohesin from chromosome arms (1).

Reference
1. Higgins, J.M. (2010) Haspin: a newly discovered regulator of mitotic chromosome behavior. Chromosoma, 119, 137-147. PMID: 19997740

    IKKs family contains four members, IKKα, IKKβ and two IKK-related kinases, IKKε and NAK, which have been identified with sequence similarity to IKKα and IKKβ. Sequence analysis of IKKs shows that IKKα and IKKβ contain a kinase catalytic domain in its N-terminal and followed by three function motif, known as LZ(leucine zipper), HLH(helix-loop-helix) and NBD(NEMO-binding domain). Activation of IKKs is associated with NF-κB signaling pathway which is triggered by different receptors, including members of TNFR family, members of the IL-1R and Toll-Like receptor (TLR) family and antigen receptors. All IKKs are implicated in the regulation of NF-κB activity and IKKs act as key regulator in various physiological and pathophysiological functions including host defense response, inflammation, cell survival, cancer, metabolic regulation, and neuroadaptation (1).

Reference
1. Hacker, H. and Karin, M. (2006) Regulation and function of IKK and IKK-related kinases. Sci STKE, 2006, re13. PMID: 17047224

    IRE family kinases are endoribonuclease that functions in the interferon (IFN) antiviral response. In INF treated and virus infected cells, family member RNASEL probably mediates its antiviral effects through a combination of direct cleavage of single-stranded viral RNAs, inhibition of protein synthesis through the degradation of rRNA, induction of apoptosis, and induction of other antiviral genes. RNASEL mediated apoptosis is the result of a JNK-dependent stress-response pathway leading to cytochrome c release from mitochondria and caspase-dependent apoptosis. Therefore, activation of RNASEL could lead to elimination of virus infected cells under some circumstances. RNASEL might also play a central role in the regulation of mRNA. turnover (1).

Reference
1. UniProt Annotation: RN5A_HUMAN

    NAK family is composed of four members. Family member MPSK is a membrane-associated protein kinase that phosphorylates on serine and threonine residues. In vitro substrates include DRG1, ENO1 and EIF4EBP1. MPSK can also autophosphorylates. In addition, MPSK may be involved in secretory vesicle trafficking or intracellular signaling and may have a role in regulating stromal-epithelial interactions that occur during ductal morphogenesis in the mammary gland. AAK1, another member, regulates clathrin-mediated endocytosis by phosphorylating the AP2M1/mu2 subunit of the adaptor protein complex 2 (AP-2) which ensures high affinity binding of AP-2 to cargo membrane proteins during the initial stages of endocytosis. Isoform 1 and isoform 2 display similar levels of kinase activity towards AP2M1. AAK1 can regulate phosphorylation of other AP-2 subunits as well as AP-2 localization and AP-2-mediated internalization of ligand complexes. Phosphorylates NUMB and regulates its cellular localization, promoting NUMB localization to endosomes. Binds to and stabilizes the activated form of NOTCH1, increases its localization in endosomes and regulates its transcriptional activity (1).

Reference
1. UniProt Annotation:   STK16_HUMAN;   AAK1_HUMAN

    NEKs (Never in mitosis A-related kinases) are classified into "Other" group. Eleven members have been identified in human genome. NimA is the founding member of the NEK family of ser/thr kinases which is an essential regulator of mitosis. All NEK kinases except NEK10 contain N-terminal catalytic domain, followed by coiled-coiled motifs except in NEK4,6 and 7 members. And in C-terminal, PEST sequences are found in moreover 6 of 11 NEK kinases. Besides the homology regions, certain NEKs contain unique domain or sequences, such as RCC1 repeats, DEAD-box helicase-like domain and armadillo repeats. NEKs play an important role in a variety of cellular processes and functions via mediate the phosphorylation of substrates. Studies show that NEK2 is essential in control of centrosome splitting, NEK6, 7 and 9 have been found in regulating mitotic spindle and cytokinesis, NEK1 and NEK8 is related to ciliagenesis. NEKs act as key regulator function during mitosis and abnormal expression or mutations on NEKs gene will lead to some disease and cancers such ovarian cancer, lung cancer, breast cancer and so on (1).

Reference
1. Moniz, L., Dutt, P., Haider, N. and Stambolic, V. (2011) Nek family of kinases in cell cycle, checkpoint control and cancer. Cell Div, 6, 18. PMID: 22040655

    NKF2 kinases belong to "Other" group. One member has been identified in human genome, PINK1 (PTEN-induced putative kinase protein 1). PINK1 gene encodes a 581-amino acid protein, which contains an N-terminal 34-amino acid mitochondrial targeting sequence (MTS), followed by a transmembrane domain (TMD) and a highly conserved kinase catalytic domain. PINK1 is a mitochondrial membrane integral protein and kinase domain localizes in the outer mitochondrial membrane and is accessible from the cytoplasm. The TMD domain is essential for anchoring PINK1 to the mitochondrial membrane and to ensure the kinase domain faces the cytoplasm. PINK1 function as a ser/thr protein kinase and mediate the phosphorylation of several substrates such as TRAP1, parkin, mTORC2 and so on. Abnormal expression or mutation of PINK1 will lead to diseases, for example PINK1-deficient Drosophila is associated with PD. In addition, PINK1 have been reported to be a key molecule in mitochondrial regulation (1).

Reference
1. Kawajiri, S., Saiki, S., Sato, S. and Hattori, N. (2011) Genetic mutations and functions of PINK1. Trends Pharmacol Sci, 32, 573-580. PMID: 21784538

    NKF4 kinases are original defined as new kinase family 3. NFK3 contains two members in human genome, PDIK1 and PDIK1L. The two kinase members are characterized by their ability to interact with PDLIM1/CLP-36. More function and regulation remains more understood (1).

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

    NKF5 kinases are original defined as new kinase family 3. NFK3 contains two members in human genome, PDIK1 and PDIK1L. The two kinase members are characterized by their ability to interact with PDLIM1/CLP-36. More function and regulation remains more understood (1).

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

    NRBP (Nuclear receptor-binding protein) belong to the "Other" group (1). One member has been identified in human genome. NRBP may play a role in subcellular trafficking between the endoplasmic reticulum and Golgi apparatus through interactions with the Rho-type GTPases. NRBP binding to the NS3 protein of dengue virus type 2 appears to subvert this activity into the alteration of the intracellular membrane structure associated with flaviviral replication (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. Uniprot annotation: NRBP_HUMAN

    PEK family is composed of four kinase members, which are eukaryotic translation initiation factor 2-alpha kinase. Family member EIF2AK1 can inhibits protein synthesis at the translation initiation level, in response to various stress conditions, including oxidative stress, heme deficiency, osmotic shock and heat shock. EIF2AK1 can exert its function through the phosphorylation of EIF2S1 at 'Ser-48' and 'Ser-51', thus preventing its recycling (1). EIF2AK2 can becomes autophosphorylated and can catalyze the phosphorylation of the translation initiation factor EIF2S1 following activation by double-stranded RNA in the presence of ATP (2). EIF2AK3 can phosphorylates the alpha subunit of eukaryotic translation-initiation factor 2 (EIF2), leading to its inactivation and thus to a rapid reduction of translational initiation and repression of global protein synthesis (3).

Reference
1. UniProt Annotation:   E2AK1_HUMAN;
2. UniProt Annotation:   E2AK2_HUMAN;
3. UniProt Annotation:   E2AK3_HUMAN;

    PLK (Polo-like kinase) belong to the "Other" group. PLKs are key regulators in cell cycle. Four members have been identified in human genomes which are known as PLK1-4. Sequence analysis show that PLKs are defined by two features: an N-terminal ser/thr protein kinase domain and a C-terminal duplicated polo-box region. Kinase catalytic is highly conserved among all PLKs while the two Polo-box regions are much less conserved which functions as a single unit named "PBD". Human PLK1 is expressed during late G2 and M phases and regulate much of the machineries which are required in mitosis. PLK2 is expressed primarily in early G1 and control the entry into S phase. The expression level of PLK3 is constant durning cell cycle and plays a important role in many stress response pathways. In addition, PLK2 and PLK3 play some similar roles with PLK1 in mitotic functions including Golgi fragmentation and cytokinesis. Like Plk1, Plk4 is essential for cell viability and studies show that PLK4 can also function as tumor suppressor protein (1).

Reference
1. Lowery, D.M., Lim, D. and Yaffe, M.B. (2005) Structure and function of Polo-like kinases. Oncogene, 24, 248-259. PMID: 15640840.

    SCY1 family is composed of three members in human genome (1). SCYL1 is involved in regulating COPI-mediated retrograde traffic. Isoform 6 acts as transcriptional activator. It binds to three different types of GC-rich DNA binding sites (box-A, -B and -C) in the beta-polymerase promoter region. It also binds to the TERT promoter region (2). SCYL2 is component of AP2-containing clathrin coated structures at the plasma membrane or of endocytic coated vesicles and may regulate clathrin-dependent trafficking between the TGN and/or the endosomal system (3).

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. UniProt Annotation:   NTKL_HUMAN;
3. UniProt Annotation:   SCYL2_HUMAN;

    Slob family contains one member in human genome which is known as PXK (PX domain-containing protein kinase-like protein). PXK consists of a ser/thr kinase catalytic domain, however several key residues that are important of intrinsic catalytic activity is absent. Human PXK have at four splice isoforms and each of them has a different subcellular localization. PXK can binds to and modulates brain Na, K-ATPase subunits ATP1B1 and ATP1B3 and play an critical role in regulation of electrical excitability and synaptic transmission (1,2).

Reference
1. Zou, X., G. Qiu, et al. (2005). "Expression pattern and subcellular localization of five splice isoforms of human PXK." Int J Mol Med 16(4): 701-707. PMID: 16142408
2. Uniprot annotation: PXK_HUMAN

    TBCK (TBC domain-containing protein kinase-like protein) are classified into "Other" group (1). One member has been found in human genome, known as TBCK. The kinase catalytic domain of TBCK is predicted to be catalytically inactive. The functions remains to be more understand.

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

    TLK (Tousled-like kinase) are classified into "Other" group (1). TLKs are originally found to encode a ser/thr kinase that is essential for proper flower development in Arabidopsis thaliana. Two homologues have been found in human genome, known as TLK1 and TLK2. Two TLKs share 84% similarity with each other and almost 50% with Arabidopsis TLK. All three TKLs contain nuclear localization signals and predicted coiled-coil regions in N-terminal. The mammalian TLKs share some similar function properties with plant TLK, including a broad expression and preference to similar substrates. In addition, human TLKs play important roles in regulation of cell cycle and reach the maximal activities in S phase (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. Sillje, H.H., Takahashi, K., Tanaka, K., Van Houwe, G. and Nigg, E.A. (1999) Mammalian homologues of the plant Tousled gene code for cell-cycle-regulated kinases with maximal activities linked to ongoing DNA replication . EMBO J, 18, 5691-5702. PMID: 10523312

    TOPK (T-LAK cell-originated protein kinase), also known as MAPKK-like protein kinase, are classified into "Other" group (1). One member has been identified in human genome. TOPK was originally found in T-LAK-Cell substraction library, highly expressed in testicular tissue. TOPK plays an important role in spermatogenesis and also expresses in hematologic tumors, including leukemia, lymphoma and myeloma. TOPK can be phosphorylated by cdk1/cyclin B and is unregulated during mitosis. More functions remain to be further understood (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. Matsumoto, S., Abe, Y., Fujibuchi, T., Takeuchi, T., Kito, K., Ueda, N., Shigemoto, K. and Gyo, K. (2004) Characterization of a MAPKK-like protein kinase TOPK. Biochem Biophys Res Commun, 325, 997-1004. PMID: 15541388.

    TTK is a mammalian homolog of conserved Mps1 family members expressed in all proliferating cells and tissues. TTK was original identified by screening of a T cell expression library with anti-phosphotyrosine antibodies. The C-terminal catalytic domains of TTKs show a high degree of sequence similarity and TTKs can function as both a ser/thr protein kinase and a tyrosine protein kinase. TTKs play an important role in regulation of cell cycle progression. Studies show that human TTK is required for human cells to undergo checkpoint arrest in response to microtubule depolymerization. In addition, TTK can exert its ecntrosome-based function by modulating TACC2 in mitosis (1).

Reference
1. Dou, Z., Ding, X., Zereshki, A., Zhang, Y., Zhang, J., Wang, F., Sun, J., Huang, H. and Yao, X. (2004) TTK kinase is essential for the centrosomal localization of TACC2. FEBS Lett, 572, 51-56. PMID: 15304323

    ULKs refer to Unc-51-like kinase which are classified into Others family. In vertebrates, at least five ULks have been found in this family and display a considerable homology to Atg1/UNC-51 in their kinase domain. Human ULK1 possesses an overall similarity of 41% to UNC-51.(1) ULK1 and ULK2 are the most closely related members of this family, sharing 78% homology of kinase domain and conserved C-terminal domain (CTD)(2). Studies show that ULK1 is critical to induce the autophagic response of cerebellar granule neurons to lowpatassium concentration in serum-free conditions.(1) ULK2 possesses the ability to compensate for the loss of ULK1 function in cell-type specific.(2) Overexpression of ULK3 is able to induce both autophagy and senescence in the human fibroblast cell line IMR90. (1)Another family member STK36 plays an important role in the sonic hedgehog pathway via regulating the activity of GLI transcription factors. Function of ULK4 remains more understood (1).

Reference
1. Alers, S., Loffler, A.S., Wesselborg, S. and Stork, B. (2012) The incredible ULKs . Cell Commun Signal, 10, 7. PMID: 22413737
2. Lee, E.J. and Tournier, C. (2011) The requirement of uncoordinated 51-like kinase 1 (ULK1) and ULK2 in the regulation of autophagy. Autophagy, 7, 689-695. PMID: 21460635

    VPS15 family contains one member mammals and yeast. The VPS15 gene encodes a protein kinase homolog that is essential for the efficient dilivery of soluble hydrolases to the yeast vacuole. VPS15 and VPS34 can interact directly with Gpa1 present at endosomes and stimulates increased production of phosphatidylinositol 3-phosphate (1).

Reference
1. Wikigenes annotation: VPS15

    WEE family contains three family members in human genome. Wee1A, one of family members, acts as a negative regulator of entry into mitosis (G2 to M transition) by protecting the nucleus from cytoplasmically activated cyclin B1-complexed CDK1 before the onset of mitosis by mediating phosphorylation of CDK1 on 'Tyr-15'. Specifically phosphorylates and inactivates cyclin B1-complexed CDK1 reaching a maximum during G2 phase and a minimum as cells enter M phase (1). WEE2 is oocyte-specific protein tyrosine kinase that phosphorylates and inhibits CDK1 and acts as a key regulator of meiosis during both prophase I and metaphase II, required to maintain meiotic arrest in oocytes during the germinal vesicle (GV) stage, a long period of quiescence at dictyate prophase I, by phosphorylating CDK1 at 'Tyr-15', leading to inhibit CDK1 activity and prevent meiotic reentry and also required for metaphase II exit during egg activation by phosphorylating CDK1 at 'Tyr-15', to ensure exit from meiosis in oocytes and promote pronuclear formation (2).

Reference
UniProt Annotation:   WEE1_HUMAN
UniProt Annotation:   WEE2_HUMAN;

    WNK family kinase are serine/threonine kinase and are classified into Others family. Four genes have been found encoding the WNK kinases in human genome, WNK1-4. WNKs function diversity in different cells and tissues. Studies show that WNKs regulate three sodium transportes, including NKCC2, NCC and ENaC. What's more, WNKs can regulate aldosterone-regulated renal outer medullary potassium channel (ROMK). WNKs can also be regarded as molecular switches that modify tansporter acitvity depending on physiological demands. Furthermore, WNKs also appear to be part of a larger kinase network, such as Ste20-related kinase SPAK and serum and glucocorticoid inducible kinase 1 (SGK1). Mutations or abnormal expression will lead to familial hyperkalemic hypertension (1).

Reference
1. Hoorn, E.J. and Ellison, D.H. (2012) WNK kinases and the kidney. Exp Cell Res, 318, 1020-1026. PMID: 22405999.

    Worm1 belong to "Other" group and it's a specific kinase family to Caenorhabditis elegans. The functions of the members remain to be studied (1).

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