Tyrosine kinase-containing

Src tyrosine kinase contains both an SH2 and an SH3 domain linked to a tyrosine kinase unit with a structure similar to other protein kinases. The phosphorylated form of the kinase is inactivated by binding of a phosphoty-rosine in the C-terminal tail to its own SH2 domain. In addition the linker region between the SH2 domain and the kinase is bound in a polyproline II conformation to the SH3 domain. These interactions lock regions of the active site into a nonproductive conformation. Dephosphorylation or mutation of the C-terminal tyrosine abolishes this autoinactivation. 

Nonreceptor protein tyrosine kinases contain a catalytic domain, as well as various regulatory domains important for proper functioning of the enzyme 416... 

Nonreceptor protein tyrosine kinases contain a catalytic domain, as well as various regulatory domains important for proper functioning of the enzyme. NRPTKs are found in the inner leaflet of the plasma membrane, cytosol, endosomal membranes and nucleus. These include the Src, Jak, Abl, Tec, Ack, Csk, Fak, Fes, Frk and Syk subfamilies (Fig. 24-3). Since a great deal is known about the structure and regulation of the Src family tyrosine kinase, we will use it to illustrate the principles in NRPTK signaling unique features in other subfamilies will be indicated... 

Removal of flexible loops within the kinase domain has also been required for some kinases. Many receptor tyrosine kinases contain an additional domain within their C-terminal lobe, referred to as the kinase-insert domain. Removal of this highly charged domain was required to obtain data quality crystals of VEGFR2 [15]. 

Pajusola, K. Aprelikova, O. Korhonen, J. Kaipainen, A. Pertovaara, L. Alitalo, R. Alitalo, K. FLT4 receptor tyrosine kinase contains seven im-mimoglobulin-like loops and is expressed in multiple human tissues and cell lines. Cancer Res., 52, 5738-5743 (1992)... 

Chan, T.A. Chu, C.A. Rauen, K.A. Kroiher, M. Tatarewicz, S.M. Steele, R.E. Identification of a gene encoding a novel protein-tyrosine kinase containing SH2 domains and ankyrin-like repeats. Oncogene, 9, 1253-1259 (1994)... 

It remains unclear whether such approaches are truly general, in particular for proteins such as receptors that span different cellular compartments. For example, some receptor tyrosine kinases contain a kringle domain in their extracellular regions. Would such protocols predict common functions for intracellular tyrosine kinases and extracellular kringle-containing proteins, such as those of the hlood coagulation pathway Nevertheless, it is apparent that considerable functional constraints exist for domains to co-occur and that domain combinations are often very limited. 

Immunreceptor based activation motif. The classical ITAM motif comprises the consensus sequence Yxxl/ Lx(6-12)YxxI/L (where Y stands for tyrosine, I stands for isoleucine, L stands for leucine, and x can be any amino acid). Kinases containing tandem SH2 domains, as for example ZAJP-70 or SYK, recognize the phosphorylated ITAMs, thereby initiating downstream signaling events. 

Besides cytoplasmic protein kinases, membrane receptors can exert protein kinase activity. These so-called receptor tyrosine kinases (RTK) contain a ligandbinding extracellular domain, a transmembrane motif, and an intracellular catalytic domain with specificity for tyrosine residues. Upon ligand binding and subsequent receptor oligomerization, the tyrosine residues of the intracellular domain become phosphory-lated by the intrinsic tyrosine kinase activity of the receptor [3, 4]. The phosphotyrosine residues ftmction as docking sites for other proteins that will transmit the signal received by the RTK. 

Protein-protein interaction domain that binds to polyproline motifs with the sequence PXXP. Particularly important in assembling protein complexes at activated receptors which contain intrinsic tyrosine kinases. 

A nucleotide exchange factor that activates Ras in response to external cues such as growth factors. Localizes to activated receptors, which contain intrinsic tyrosine kinases, through its interaction with the adaptor protein Grb-2. 

The Src-homology 2 (SH2) domain is a protein domain of roughly 100 amino acids found in many signaling molecules. It binds to phosphorylated tyrosines, in particular peptide sequences on activated receptor tyrosine kinases or docking proteins. By recognizing specific phosphorylated tyrosines, these small domains serve as modules that enable the proteins that contain them to bind to activated receptor tyrosine kinases or other intracellular signaling proteins that have been transiently phosphorylated on tyrosines. 

PTKs can be subdivided into two large families, receptor tyrosine kinases (RTKs) and non-RTKs. The human genome encodes for a total of 90 tyrosine kinases of which 32 are nonreceptor PTKs that can be placed in 10 subfamilies (Fig. 1). All nonreceptor PTKs share a common kinase domain and usually contain several additional domains that mediate interactions with protein-binding partners, membrane lipids, or DNA (Table 1). These interactions may affect cellular localization and the activation status of the kinase or attract substrate proteins for phosphorylation reactions. 

HSFl phosphorylation must be sensitive to nonheat inducers of HSF-DNA binding activity because HSFl phosphorylation can be achieved at 37 °C by other inducers of the HS response. HSF 1 contains polypeptide sequences that could serve as substrates for well characterized protein kinases, but few of these are known to be heat inducible. One family of protein kinases, the S6 protein kinases, have already been shown to exhibit heat inducible activity however, their peak level of activity during HS occurs well after the maximal induction of HSF phosphorylation (Jurivich et al., 1991). Thus, other protein kinases are likely to be directly linked to the phosphorylation of HSF. Some of the putative protein phosphorylation sites on HSF include motifs for protein kinase C, casein kinase, and enterokinase. There are tyrosine sequences that match substrates for known tyrosine kinases, but whether these residues are accessible to phosphorylation is not established. 

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