STATs signal transducers and activators

Ihle, J. 1996. STATs signal transducers and activators of transcription. Cell 84, 331-334. 

Leptin signalling is via monomeric receptors in the brain. A short-form of the leptin receptor (Lep-R) is required to transport the hormone across the blood-brain barrier and a long-form Lep-R is located in the hypothalamus. The long-form is functionally linked with a particular type of receptor-associated tyrosine kinase called Janus kinase (JAK, see Section 4.7) whose function is to phosphorylate a STAT (signal transducer and activator of transcription) protein a similar mechanism to that often associated with signalling by inflammatory cytokines. 

Starting from the activated Jak kinases, a signaling pathway leads directly to transcription factors that are phosphorylated by the Jak kinases on tyrosine residues and activated for stimulation of transcription (review Horvath and Darnell, 1997). These transcription factors belong to a class of proteins known as Stat proteins (Stat = signal transducer and activator of transcription). At least seven different Stat proteins are known (Statl-4, StatSa, StatSb, Stat6). The first Stat proteins, Statl and Stat2, were foimd in association with signal transduction via interferon y. 

Fig. 3. A simplified illustration of BCR-ABL and SRC family kinase involvement in oncogenic signaling pathways. The inhibitory effect is indicated by the upside-down T s. ABL = Abelson tyrosine kinase BCR = breakpoint cluster region FAK = focal adhesion kinase Grb-2 = growth factor receptor-bound protein 2 HcK = hematopoietic cell kinase JNK = Jun amino-terminal kinase P = phosphate group PI3 K = phosphatidylinositol-3-kinase SFK = SRC family kinases StatS = signal transducer and activator of transcription 5. (Reprinted with permission from Ref (123)). 

A variation on the basic theme of receptor Tyr kinases is seen in receptors that have no intrinsic protein kinase activity but, when occupied by their ligand, bind a soluble Tyr kinase. One example is the system that regulates the formation of erythrocytes in mammals. The cytokine (developmental signal) for this system is erythropoietin (EPO), a 165 amino acid protein produced in the kidneys. When EPO binds to its plasma membrane receptor (Fig. 12-9), the receptor dimerizes and can now bind the soluble protein kinase JAK (Janus kinase). This binding activates JAK, which phosphory-lates several Tyr residues in the cytoplasmic domain of the EPO receptor. A family of transcription factors, collectively called STATs (signal transducers and activators of transcription), are also targets of the JAK kinase activity. An SH2 domain in STATS binds (P)-Tyr residues in the EPO receptor, positioning it for this phosphorylation by JAK. When STATS is phosphorylated in re-... 

Fig. 20.1 Leptin receptor isoforms. Leptin receptor isoforms (Ob-Ra to Ob-Re) are the result of alternative gene splicing. Ob-Rb is considered to be the active isoform for carrying out downstream signaling. The extracellular region of the receptor is comprised of two CK (cytokine receptor domain) and three F3 (fibronectin domain) domains. The extracellular domain is followed by the transmembrane domain. The intracellular region consists of B1 (box 1) and B2 (box 2) for JAK2 binding and STAT (signal transducers and activators of transcription) binding domain.

STATs (signal transducers and activators of transcription) transmit signals primarily from cytokines (see Chapter 6).36 Seven mammalian stat genes have been identified up to now and localized on chromosomes. Splicing of the pre-messenger RNA may lead to additional variants. STAT 2 participates (jointly with STAT 1) only in IFN-cc/p signalling.3T STAT 2 is present in nearly all cells, whereas the distribution of STAT 4 and STAT 5 is more restricted. STAT 4 is expressed in myeloid cells, where it is induced by IL-4 signals and where it participates in early myeloid differentiation.38,39 STATs have... 

STAT Signal transducers and activators of transcription, proteins which are involved in the development and... 

STAT signal transducers and activators of TRANCE TNF-related acdvadon-induced cytokine... 

JAK-STAT pathway a signaling pathway utilized by cells to respond to cytokines and growth factor stimuli. This pathway transduces the signals carried by cytokines to the cell nucleus, where activated STAT proteins modify gene expression. JAKs—Janus Kinases STATs—Signal Transducers and Activators of Transcription. 

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