ABL kinases consist of protein kinase catalytic domain and Src homology domains SH3 and SH2. However, the cellular ABL kinase(c-Abl) is different from Src tyrosine kinase. First, c-Abl can localize both in cytoplasmic and nuclear compartments. Second, c-Abl can interact with the cytoskeleton via its binding sites for F-actin and G-actin. Third, c-Abl can be associated with chromatin via its three HMG-like boxes which mediate the binding with A/T diplexes and distorted DNA structure. c-Abl play an important role in many processes associated with cell growth and survival. c-Abl knockout mice will exhibit embrynoic and neonatal lethality which can be rescued by the transgenic expression of c-Abl cDNA. Studies show that c-Abl has an active role in the induction of cell death. In addtion, ABL kinase possesses the oncogenic potential which can be activated in the Bcr-Abl fusion protein of chronic myelogenous leukemia (1).

Reference
1. Wang, J.Y. (2000) Regulation of cell death by the Abl tyrosine kinase. Oncogene, 19, 5643-5650 PMID: 11114745

    Ack family is non-receptor tyrosine kinases. Two genes encode Ack have been found in human genome, known as TNK1 and Ack1 (TNK2). Sequence analysis of Acks show that Ack family consist of an N-terminal sterile alpha motif (SAM) domain, followed by a kinase catalytic domain and an SH3 domain. Certain Ack contains a Cdc2/Tac-interactive domain (CRIB). Acks are unique NRTKs with SH3 domain located c-terminal to kinase domain. The first member Ack1 was originally cloned from a human hippocampal expression library. Ack1 gene is located on chromosome 3q29 in human, where a region is associated with recurrence of prostate cancer and is a predictor of metastatic relapse in breast cancer.TNK1 was originally cloned from hematopoietic stem/progenitor cells. TNK1 have been reported to block NF-kB activation and promotes apoptosis mediated by TNFα signaling pathway (1).

Reference
1. Prieto-Echague, V. and Miller, W.T. (2011) Regulation of ack-family nonreceptor tyrosine kinases. J Signal Transduct, 2011, 742372. PMID: 21637378

    Axl family also refer to TAM family which consists of Tyro-3, Axl and Mer. TAM family are receptor tyrosine kinases characterized by a conserved sequence within the kinase domain and adhesion molecule-like extracellular domains. The sequence analysis shows that TAM kinase share 31%-36% identical amino acids within the extracellular region and 54%-59% identity within intracellular domain. TAM kinase can produce diverse cellular functions via combining with different ligand and in different cell types. The loss of TAM receptor in macrophages/dendritic cells will lead to autoimmune diseases including rheumatoid arthritis and lupus. In Nautre killer cells (NK cells), TAM receptor is essential for normal differentiation and functional maturation of NK cells. In platelets, TAM receptor is required for platelets aggregation. TAM kinases also executive function via several signaling pathway. MER and Axl signaling lead to platelet aggregation, cell survial, regulation of proinflammatory ctyokine production and regulation of the actin cytoskeleton. Tyro-3 signaling pathway also mediates the cell transformation and osteoclastic bone resorption. Mutation or abnormal expression of TAM kinases will cause some diseases, and several studies have validated the therapeutic potential of targeting the TAM family in cancer therapy (1).

Reference
1. Linger, R.M., Keating, A.K., Earp, H.S. and Graham, D.K. (2008) TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. Adv Cancer Res, 100, 35-83. PMID: 18620092

    CCK4 (Colon Carcinoma Kinase 4), which is known as protein tyrosine kinase-7 (PTK7), is a human homologue of KLG. PTK7 contains an extracellular domain, seven immunoglobulin-like loops and an inactive catalytic domain of tyrosine kinase. Studies show that PTK7 act as a novel regulator of planar cell polarity in vertebrates (1). PTK7 can also recruit dsh to regulate neural crest migration (2). In addition, several alternatives splicing of PTK7 mRNA may contribute to its diverse functions in cell signaling (3).

Reference
1. Lu, X., Borchers, A.G., Jolicoeur, C., Rayburn, H., Baker, J.C. and Tessier-Lavigne, M. (2004) PTK7/CCK-4 is a novel regulator of planar cell polarity in vertebrates. Nature, 430, 93-98. PMID: 15229603
2. Shnitsar, I. and Borchers, A. (2008) PTK7 recruits dsh to regulate neural crest migration. Development, 135, 4015-4024. PMID: 19004858
3. Jung, J.W., Ji, A.R., Lee, J., Kim, U.J. and Lee, S.T. (2002) Organization of the human PTK7 gene encoding a receptor protein tyrosine kinase-like molecule and alternative splicing of its mRNA. Biochim Biophys Acta, 1579, 153-163. PMID: 12427550

    Csk family contains two members in human genome. Family member MATK could play a significant role in the signal transduction of hematopoietic cells. MATK may regulate tyrosine kinase activity of SRC-family members in brain by specifically phosphorylating their C-terminal regulatory tyrosine residue which acts as a negative regulatory site. It may play an inhibitory role in the control of T-cell proliferation (1). CSK, another family member, is a non-receptor tyrosine-protein kinase that plays an important role in the regulation of cell growth, differentiation, migration and immune response. Phosphorylates tyrosine residues located in the C-terminal tails of Src-family kinases (SFKs) including LCK, SRC, HCK, FYN, LYN or YES1. Upon tail phosphorylation, Src-family members engage in intramolecular interactions between the phosphotyrosine tail and the SH2 domain that result in an inactive conformation. To inhibit SFKs, CSK is recruited to the plasma membrane via binding to transmembrane proteins or adapter proteins located near the plasma membrane. CSK can also suppresses signaling by various surface receptors, including T-cell receptor (TCR) and B-cell receptor (BCR) by phosphorylation and maintaining inactive several positive effectors such as FYN or LCK (2).

Reference
UniProt Annotation: MATK_HUMAN
UniProt Annotation: CSK_HUMAN

    DDR (Discoidin domain receptor) belong to receptor tyrosine kinase. DDRs exist in all animals. Two genes encoding DDR1 and DDR2 have been found in mammals. DDRs possess a typical RTK structure, including a signal peptide, an extracellular region, a transmembrane domain and an intracellular kinase domain. The discoidin domain exists in extracellular domain and mediates the collagen-binding. DDR1 is overexpressed in several cancers and is a direct transcriptional target of p53. Studies show that DDR1 can regulate cell spreading and motility by associating with myosin IIA and can also regulate the stabilization of cell surface E-cadherin and E-cadherin-mediated cell aggregation (1). DDR2 can act as a cell surface receptor for fibrillar collagen, and can regulate cell differentiation, remodeling of the extracellular matrix, cell migration and cell proliferation (2).

Reference
1. Huang, Y., Arora, P., McCulloch, C.A. and Vogel, W.F. (2009) The collagen receptor DDR1 regulates cell spreading and motility by associating with myosin IIA. J Cell Sci, 122, 1637-1646. PMID: 19401332
2. Uniprot annotation:   DDR2_HUMAN

    EGFRs (Epidermal growth factor receptors) are transmembrane receptor tyrosine kinases. Four members have been identified in human, EGFR/ErbB-1, HER2/ErbB-2, HER3/ErbB-3 and HER4/ErbB-4. EGFRs consist of an extracellular ligand-binding domain and a cytoplasmic region containing a kinase domain. EGFRs can be activated via binding some EGF-like molecules, TGF-α and neuregulins to extracellular domain. Ligand binding can also induce the formation of receptor homodimers or heterodimers, which will lead to some phosphorylation of tyrosine residues on one receptor, and provide docking sites for downstream signal molecules. The EGFR signaling network is highly complex, signal will be transducted from cell surface into nucleus through a variety of molecules. The signaling network will finally affect several cellular processes, including cell apoptosis, cell migration, cell growth, cell adhesion and differentiation (1).

Reference
1. Yarden, Y. (2001) The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities. Eur J Cancer, 37 Suppl 4, S3-8. PMID:11597398

    Eph receptor tyrosine kinases are known able to bind their ephrin ligands and act as key regulator of cell contact-dependent signaling and patterning. Eph kinase contains fourteen members which can further be classified into two subclasses A and B in human. EphA1-8 and Eph10 belong to subclass A, EphB1-4 and EphB6 belong to subclass B. Eph kinases consist of two regions: intracellular region and extracellular region. The extracellular part contains a globular ligand-binding domain, a cysteine-rich region and two fibronectin type III repeats. The intracellular part contains a short juxtamembrane region, a kinase catalytic domain, a sterile α motif (SAM) protein−protein interaction domain and a PDZ-binding motif. Eph/ephrin binding will lead to very diverse biological readouts including adhesion versus repulsion and increased versus decreased motility. Depending on the different cell type and context, the interaction will lead to different downstream signaling pathway. In addition, evidence shows that endocytosis of Eph/ephrin and associated tissue-specific effectors are essential for diverse biological roles and processes (1).

Reference
1. Pitulescu, M.E. and Adams, R.H. (2010) Eph/ephrin molecules--a hub for signaling and endocytosis. Genes Dev, 24, 2480-2492. PMID: 21078817

    FAKs are ubiquitously expressed non-receptor protein-tyrosine kinase. Two members have been found in human genome FAK1 and FAK2. FAKs contain a FERM domain at N-terminal followed by a protein kinase domain and a C-terminal FAT domain. FERM domain mediate the directly bind to intracellular domain of β1-integrin subunit or some membrane receptor. FERM domain is also responsible for FAK kinase catalytic activity regulation. FAT domain is responsible for FAK binding to focal adhesion complexes. FAKs keep an inactive conformation in which FERM is bound to FAK kinase domain. After release the auto-inhibitory between FERM and kinase domain, FAKs will undergo kinase activation and autophosphorylation of Y397, which will in turn produce the maximal activity. Activate FAKs will function on different substrates and lead to different effects on cell behaviors, including increased motility, integrin recycling, focal contact turnover, survival and protection from adhesion dependent apoptosis (anoikis) (1).

Reference
1. Lechertier, T. and Hodivala-Dilke, K. (2012) Focal adhesion kinase and tumour angiogenesis. J Pathol, 226, 404-412. PMID: 21984450

    FGFR (Fibroblast growth factor receptor) are receptor tyrosine protein kinase and involved in FGF signaling. FGFRs contain an extracellular domain which can directly bind to FGF ligand, a transmembrane and intracellular kinase domain. The combining of extracellular domain and ligand will lead to the phosphorylation of several tyrosine residues within their intracellular domains and this will increase the kinase activity of FGFRs. Activated FGFRs can interact with downstream molecules, such as PLC-1 and Crk and activate related signaling cascades pathway, which regulate distinct biological process including proliferation, differentiation, cell survival, protein synthesis, angiogenesis, cell growth and cell migration (1).

Reference
1. Acevedo, V.D., Ittmann, M. and Spencer, D.M. (2009) Paths of FGFR-driven tumorigenesis. Cell Cycle, 8, 580-588. PMID: 19182515

    InsR (insulin receptor) are receptor tyrosine protein kinase found across a wide spread of organisms and play an essential role in glucose homeostasis. InsRs consist of two subunits A and B. The A subunit is a 135kD extracellular and the 95 kD B subunit contains a extracellular domain, a transmembrane domain and an intracellular tyrosine kinase domain. The combine of receptor and ligand will lead to the InsR autophosphorylation and then become active. Activated InsRs will mediate the phosphorylation of downstream substrates, including IRS, Gab-1, Shc and Cbl, which involved in MAPK or PI3K signaling pathway (1).

Reference
1. http://www.cellsignal.com/pdf/7748.pdf

    Jak (Janus kinase) are tyrosine protein kinase. Four members have been found in human genome, known as Jak1-3 and TYK2. TYK2 was the first screened from a T-cell library using low stringency hydridization techniques. Jak1-3 were subsequently cloned. Human Jak1, Jak2 and TYK2 localize on chromosomes 1p13.3, 9p24 and 19p13.2. Jak3 was further mapped to human chromosome 19p131. Jaks contain several JAK homology regions (JH1-JH7). Two kinase domains have been found in Jaks. The C-terminal kinase domain (JH1) posses the catalytic ability and another domain is likely to be catalytic inactive. The N-terminal domain of Jaks often mediates the interaction with cytokine/interferon/growth hormone receptors. The Jaks is original being inactive state and recruited to several receptors and subsequently get activated via auto-phosphorylation or phosphorylation by others Jaks. Activated Jaks will mediate the phosphorylation and activation Signal Transducers and Activators of Transcription (STAT) which will translocate to nucleus and regulate the gene expression. In addition, Jaks also mediate the recruitment of other molecules involved in signal transduction including src-family kinases, protein tyrosine phosphatases, MAP kinases, PI3 kinase. These molecules will also result in the activation of transcription factors and gene expression (1).

Reference
1. Rane, S.G. and Reddy, E.P. (2000) Janus kinases: components of multiple signaling pathways . Oncogene, 19, 5662-5679. PMID: 11114747

    Met kinase, also known HGF/SF receptor, belong to receptor tyrosine family. Met is a heterodimer containing an extracellular α-subunit which bond to a transmembrane β-subunit. The β-subunit also possess the intracellular catalytic activity. In addtion, extracellular regions also contain two functional regions, the PSI domain and four conserved IPT domains. The intracellular segment contains a Juxtamembrane sequence, a catalytic region and multifunctional docking sites. Several key tyrosine residues have been identified to be involved in kinase activation or recruitment of other transducers and adaptors. The Met is responsible for the signal transduction from cell membrane to cytoplasm via different signaling pathway, including the MAPK cascades, the PI3K-Akt axis, the STAT pathway and the CNF-κB pathway etc. Met singalings play an important roles in development and disease. Via signal transduction to distinct adaptors, Met mediate the regulation of embryonic development, organ regeneration and even tumorigenesis (1).

Reference
1. Trusolino, L., Bertotti, A. and Comoglio, P.M. (2010) MET signalling: principles and functions in development, organ regeneration and cancer. Nat Rev Mol Cell Biol, 11, 834-848. PMID: 21102609

    PDGFR (Platelet-derived growth factor receptor) are receptor tyrosine kinase. Two different gene encoding PDGFR-A and PDGFR-B have been identified in human genome, both of which can interact with PDGFs to regulate diverse cellular processes. PDGFRs contain similar structure, including five extracellular immunoglobulin loops and an intracellular kinase domain. PDGFRs are original inactive in unstimulated cell environment. Ligand binding leads to the dimerization of PDGFR which will mediate the autophosphorylation on tyrosine residues in intracellular domain. Activate PDGFR subsequently target the downstream signaling molecules via the docking sites and further lead to the protein-protein interactions. Via targeting to distinct molecules, PDGFRs are involved in diverse signaling pathway, including JNK/SAPK and RAS/MAPK, and some secondary effectors such as Akt, JNK, PKC and p70S6K (1).

Reference
1. Andrae, J., Gallini, R. and Betsholtz, C. (2008) Role of platelet-derived growth factors in physiology and medicine. Genes Dev, 22, 1276-1312. PMID: 18483217

    ROR kinases are receptor tyrosin kinase. Two members have been identified in human genome, ROR1 and ROR2. Sequence analysis shows that RORs share conserved domain structure. The extracellular region contains a immunoglobulin domain, a cysteine-rich region and kringle domains. The intracellular region contains a tyrosine kinase domain and two serine and threonine rich region. Studies show ROR genes play an important role during development. ROR2 knockouts mouse display differentiation defects in growth plate, which suggests mROR2 is essential for regulation of proliferation. Function loss of ROR2 in human will cause the defects in endochondral bone formation. In C. elegans, ROR family has been found to be required for proper cell migration, development of ASI (1).

Reference
1. Forrester, W.C. (2002) The Ror receptor tyrosine kinase family. Cell Mol Life Sci, 59, 83-96. PMID: 11846036

    Ryks are atypical receptor tyrosine kinases. One member have been found in human genome, known as Ryk. Ryk contains a Wnt inhibitory factor domain in its extracellular region, an intracellular kinase catalytic domain and a PDZ motif. However, as several mutations have been found on critical conserved tyrosine residue in kinase domain, Ryk might loss the kinase catalytic activity. The Drosophila Ryk was originally identified to be associated with learning and memory. Lin-18, the C.elegans homolog, is essential for establishing the secondary vulval cell linage polarity. Lin-18 also has a genetic interaction of Frizzled durning vulval development. Ryk knockout on mice will cause the rapid death after birth and display a cleft of the secondary palate with a abnormal craniofacial appearance. In addition, Ryk is also involved in Wnt signaling pathway, in which Ryk can bind Wnt-1 and Wnt-3a and is required for the activation of TCF. Active TCF will subsequently lead to Wnt-3a activation which is important in induce neurite outgrowth (1).

Reference
1. Lu, W., Yamamoto, V., Ortega, B. and Baltimore, D. (2004) Mammalian Ryk is a Wnt coreceptor required for stimulation of neurite outgrowth. Cell, 119, 97-108. PMID: 15454084

    Src family kinases, also caller SFK, are receptor tyrosine protein kinase and play an essential role in regulation of signal transduction form cell surface to cytoplasm. SFK members share a conserved domain structure, including a myristoylated N-terminal segment, a SH3, SH2, linker, followed by a tyrosine kinase domain and a C-terminal short tail. The intact state of SFKs are catalytic inactive, and how these kinase assemble into a active signaling complexes with others proteins is still unresolved. SFKs can mediate the transduction of signal and regulate specialized cellular functions. In central nervous system (CNS), SFKs have been found widely expressed and are involved in proliferation and differentiation of CNS through upregulating the activity of NMDA receptors and other ion channels. In T-cell antigen receptor signal transduction, SFKs interact with TCR via association with CD4 and CD8 co-receptor, Unc119 and so on, which will regulate the proliferation of T cells. SFKs are also involved in initiating signal transductino via the B-cell antigen receptor. The function loss of SFKs will lead to the defects in B-cell development and autoimmunity (1).

Reference
1. Parsons, S.J. and Parsons, J.T. (2004) Src family kinases, key regulators of signal transduction. Oncogene, 23, 7906-7909. PMID: 15489908.

    Syk (Spleen tyrosine kinase) belong to tyrosine protein kinase. Two members have been found in human genome, Syk and ZAP70. Syks contain two SRC homology 2 (SH2) domains and a C-terminal tyrosine kinase domain. Syks is intact catalytic inactive, and can be activated after binding of SH2 domains to phosphorylated ITAMs, or phosphorylation of tyrosine residues in linker regions. Syk is involved in integrin mediated signaling pathway and activated by integrins, active Syk is essential for firm leukocyte adhesion to the inflamed endothilium and development of MAC1-dependent vasculopathy reaction. Syk is also involved in innate pathogen recognition, including recognition of fungi, inflammasome activation, recognition of bacteria and viruses, signaling tissue damage and other immune functions. In addition, Syk act as a key molecule in regulation of bone metabolism, platelet functions, vascular development and other non-haematopoietic functions. Syk deficient or abnormal expressions will lead to some allergic or autoimmune diseases. What's more, Syk is also found to be required for the oncogenic activity of several viruses which can promote some virus-induced tumours development (1).

Reference
1. Mocsai, A., Ruland, J. and Tybulewicz, V.L. (2010) The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat Rev Immunol, 10, 387-402. PMID: 20467426

    Tec family kinases (TFK) represent the second largest family of non-receptor protein tyrosin kinases. Five members have been identified in human genome, Etk, Itk, Rlk, Btk and Tec. The expression of TFKs is mainly in immune system, Btk, Itk and Tec are expressed in mast cells, and some members are also found outside the hematopoietic system. TFKs are intact catalytic inactive and are recruited to membrane via the binding of PH domain to PtdIns(3,4,5)P3 phosphate. In turn, they are phosphorylated bu Src family kinases and subsequently undergo the autophosphorylation which will lead to the full activation. Activate TFKs are involved in a variety of cellular processes or signaling pathway, including cell adhesion and migration, actin reorganization, Ca2+ mobilization, apoptosis, and gene expression and transformation (1).

Reference
1. Takesono, A., Finkelstein, L.D. and Schwartzberg, P.L. (2002) Beyond calcium: new signaling pathways for Tec family kinases. J Cell Sci, 115, 3039-3048. PMID: 12118060

    Tie family belong to the receptor tyrosine kinase. Two members have been found in human genome, Tie1 and Tie2. Sequence analysis show that Tie kinases contain an extracellular region which consists of two immunoglobulin(lg)-like domains with one incomplete, the two lg-like domains are separated by three EGF-like cysteine repeats, three fibronectin type III homology domains locate proximally to membrane. The intracellular region contains the tyrosine protein kinase domains (1). Tie1 and Tie2 play an important role on regulation of endothelial cell proliferation, migration and survival during angiogensis. Tie2 has also been found to be involved in vascular abnormalities. In addition, Tie2 can maintain the hematopoietic stem cells's population and quiescent status. Tie2 is also associated with several cancers and overexpression has been identified in tumoral vessels (2).

Reference
1. Jones, N., Iljin, K., Dumont, D.J. and Alitalo, K. (2001) Tie receptors: new modulators of angiogenic and lymphangiogenic responses. Nat Rev Mol Cell Biol, 2, 257-267. PMID: 11283723
2. Martin, V., Liu, D., Fueyo, J. and Gomez-Manzano, C. (2008) Tie2: a journey from normal angiogenesis to cancer and beyond. Histol Histopathol, 23, 773-780. PMID: 18366015