IRAK (Interleukin-1 receptor-associated kinase) belong to TKL family. Four genes encoding IRAKs have been identified in human genome, IRAK1, IRAK2, IRAK3 (IRAKM) and IRAK4. All IRAKs are involved in activating transcript factor NF-kB. IRAK1 has two signature forms with one unmodified 85kD form localized mainly in cytoplasm and 100kD form in nucleus. This suggests that the modification may be essential for IRAK1 trafficking from cytoplasm into nucleus and performs the function. Studies show that IRAK1 can mediate the activation of STAT3 which is important for the expression of IL-10 gene; moreover evidence also indicates that IRAK1 can directly bind to the promoter of IL-10 gene and regulate the expression. IRAK2 gene encodes a 590-amino acid protein with the size of 65kD. Overexpression of IRAK2 can be associated with MyD88 and TRAF6 and mediate the activation of NF-kB. IRAK2 is also involved in regualtion of cellular apoptosis. IRAKM gene encodes a 596-amino acid and 68kD protein. IRAKM expression has been identified in the peripheral blood leukocytes and monocytic cell lines. Overexpression of IRAKM also actives NF-kB. IRAK4 gene encodes a 460-amino acid and 52kD protein kinase. IRAK4 knockout mice display the defects of NF-kB activation and various inflammatory cytokines expression. Evidence also shows that IRAK4 is the primary kinase in the TLR signaling pathway and key regulator for the NF-kB activation. IRAK4 defect always associated with human disease, including persistent pyogenic bacteria infection and poor inflammatory responses (1).

Reference
1. Huang, Y.S., Misior, A. and Li, L.W. (2005) Novel role and regulation of the interleukin-1 receptor associated kinase (IRAK) family proteins. Cell Mol Immunol, 2, 36-39. PMID: 16212909

    LISK contains two subfamilies, LIMK and TESK. LIMKs refer to LIM domain kinase, and two genes encode LIMKs have been indentified in human genome, LIMK1 and LIMK2, which locate on human chromosomes 7q11.23 and 22q12.2 respectively. LIMKs have a common structure with two LIM domains in N-terminal, followed by a PDZ domain and a serine/proline rich region and a protein kinase in C-terminal. Sequences analysis show that LIMK1 and LIMK2 share a 50% overall identity and 70% identity in kinase domain. PDZ domain is involved in protein-protein interaction. LIMKs are activated via the phosphorylation of conserved threonine residues of activation loop by ROCK. LIMKs are most characterized by their ability to phosphorylate and consequent deactivate cofilin family proteins, which will lead to the actin cytoskeleton reorganization. LIMKs have been found in mediate the regulation of cell morphology and motility. Moreover, LIMKs also participate in control of cell cycle and regulation of several gene transcriptions. (1)Another subfamily is TESK. Two members have been identified in human genome, TESK1 and TESK2. TESKs contain an N-terminal protein kinase domain and C-terminal prolin-rich domain. Sequences of TESKs are similar to LIMKs. TESKs play an important role at and after meiotic phase of spermatogenesis (2).

Reference
1. Scott, R.W. and Olson, M.F. (2007) LIM kinases: function, regulation and association with human disease. J Mol Med (Berl), 85, 555-568. PMID: 17294230
2. Wikipedia annotation:     TESK1

    LRRK (leucine-rich repeat kinase) belong to TKL family. Two members have been identified in human genome, LRRK1 and LRRK2. LRRK genes are most characterized by their association with Parkinson's Disease (PD). Most frequent mutation is G2019S in LRRK2 in North America and Europe which accounts for up to 10% in family cases and up to 2% in sporadic cases. LRRK2 mutations in PD are as high as 40% in North Africans and Ashkenazi Jews. LRRKs are expressed in development and adulthood, with identical levels of LRRKs mRNA in the lung, skeletal muscle, lymph node and heart. While more LRRK2 can be identified in kidney and brain tissue. LRRKs can mediate the phosphorylation of a variety of substrates and may play a critical role in cell function (1).

Reference
1. Biskup, S., Moore, D.J., Rea, A., Lorenz-Deperieux, B., Coombes, C.E., Dawson, V.L., Dawson, T.M. and West, A.B. (2007) Dynamic and redundant regulation of LRRK2 and LRRK1 expression. BMC Neurosci, 8, 102. PMID: 18045479

    MLKs (Mixed-lineage kinases) are ser/thr protein kinases which are involved in regulation of JNK and p38 MAPK pathways. MLKs contains threes subfamily, MLK, DLK and ZAK. MLK subfamily is characterized by an N-terminal SH3 domain, followed by a protein kinase domain, a leucine-zipper region and a CRIB motif. DLK subfamily contains a kinase domain and two leucine-zipper motifs. ZAK subfamily consists of a kinase domain and a SAM domain. MLKs play an important role in regulation of JNK pathways in mammalian cells which will result in diverse biological processes, including cellular transformation, activation of NF-kB pathways, neuronal apoptosis and so on (1).

Reference
1. Gallo, K.A. and Johnson, G.L. (2002) Mixed-lineage kinase control of JNK and p38 MAPK pathways. Nat Rev Mol Cell Biol, 3, 663-672. PMID: 12209126

    RAF kinases are serine/threonine kinase and belong to TKL family. Sequence analysis of RAF kinase shows that three conserved domain is present in RAFs, known as CR1-3. CR1 contains two Ras binding domains (RBD and CRD), serine/threonine are rich in CR2 and CR3 contains a protein kinase catalytic domain. RAFs are key regulator involved in RAS-RAF-MEK-ERK signal transduction cascade, also known as MAPK cascade. RAS is activated by GTPase via a multistage process. Activate RAFs will subsequently lead to the activation of MEK1 and MEK2 and transduce the signal to downstream molecules (1).

Reference
1. Roskoski, R., Jr. (2010) RAF protein-serine/threonine kinases: structure and regulation. Biochem Biophys Res Commun, 399, 313-317. PMID: 20674547

    RIPK (Receptor-interacting protein kinase) are a group of serine/threonin protein kinases. Five members have been identified in human genome. RIPKs share a conserved kinase domain. RIPK1contain a C-terminal death domain and RIPK2 contains a caspase activation and recruitment domain (CARD). RIPK4 and RIPK5 contain a C-terminal ankyrin repeats (ANK) domains. The C-terminal region of RIPK3 is unique and diverse from other members. RIPK1 is designated as "receptor-interacting" protein. RIPK1 can bind to several death receptors via its deat domain. RIPK1 is expressed in many tissues and the expression is important for T-cell survival, studies show that lacking of RIPK1 will lead to the apoptosis in lymphoid tissue. RIPK2 plays an important in activation of p38 MAPK in the stressed heart. In addition, RIPK2 is also involved in regulation of the NF-kB signaling pathway. RIPK3 can mediate the activation of NF-kB as well and moreover, RIPK3 can directly interact with glycogen phosphorylase (PYGL), glutamate dehydrogenase 1 (GLUD1) and glutamate ammonia ligase (GLUL), and enhance its enzymatic activity. Overexpression of RIPK4 will cause the activation of NF-kB and JNK signaling and overexpression of RIPK5 will lead to cell death (1).

Reference
1. Zhang, D., Lin, J. and Han, J. (2010) Receptor-interacting protein (RIP) kinase family. Cell Mol Immunol, 7, 243-249. PMID: 20383176

    STKR are serine/threonine kinase receptor comprising two subfamily, TGFb receptors and activin receptors. TGFb receptors contain different isoforms which are homo- or heterodimeric. The mediate the interaction between ligand and receptor. TGFb receptors are expressed in diverse tissues, including heart, liver, kidney, brain and testes. TGFb receptor can be further classified into three subclasses from type1 to type3. Abnormal expression of TGFb receptor leads to renal fibrosis which will result in kidney disease. Diabetes is also found to be associated with TGFb receptor (1). Another subfamily is activin receptors, which are characterized by its feature to bind activin. The activin receptors contain a transmembrane domain and a hydrophilic Cys-rich ligand-binding domain (2).

Reference
1. Wikipedia annotation: TGF beta receptors
2. Wikipedia annotation: Activin receptor