Receptor Tyrosine Kinases

 Receptor tyrosine kinases (RTKs) are enzyme-linked receptors localized at the plasma membrane containing an extracellular ligand binding domain, a transmembrane domain, and an intracellular protein–tyrosine kinase domain. In general, the ligands for RTKs are proteins such as IGF, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and FGF. Ephrins that bind to Eph receptors also form a large subset of RTK ligands. Colony-stimulating factor 1 (CSF-1), which is important for macrophage function, is another example of an RTK ligand. RTKs can function as monomers or multimeric subunits assembled at the plasma membrane that, upon ligand binding, cause oligomerization or conformational changes followed by tyrosine (trans)-phosphorylation in the kinase activation loop. Activation of RTKs results in phosphorylation of additional sites in the cytoplasmic part of the receptor, leading to docking of protein substrates, which initiates the intracellular signaling cascade. These substrates bind to RTK-phosphorylated tyrosines through Src homology-2 (SH2) domain or phosphotyrosine-binding (PTB) domains. Examples of these types of proteins are insulin receptor substrates or the p85 regulatory subunit of PI3K. RTKs recruit, assemble, and phosphorylate different proteins, including adaptors and enzymes.

There are mechanisms to terminate ligand-induced RTK activity through cellular processes including receptor-mediated endocytosis and/or through a family of regulated protein tyrosine phosphatases (PTPs), some of which are transmembrane and have extracellular domains, suggesting the possibility of ligand-mediated regulation. Interestingly, there is also intracellular regulation of PTPs through negative-feedback loops to attenuate the signal or direct control through reactive oxygen species (ROS) (see later discussion).

Phosphatidylinositol 3-Kinase Pathway

 One of the key signaling components associated with RTKs is the PI3K signaling transduction pathway. This pathway is also activated by cytokine receptors and G protein–coupled receptors (GPCRs). Among the many functions of this pathway in hematopoietic cells, the interleukin-3 (IL-3)-dependent survival of these cells largely depends on activation of the PI3K pathway. PI3K is a heterodimeric complex formed of a regulatory and a catalytic subunit. The regulatory protein subunits are encoded by isoforms (which include p85α and p85β) that contain SH3-binding domains that mediate binding to activated RTKs. This binding allows additional recruitment and activation of the PI3K catalytic subunits (p110α, p110β, and p110*). At the plasma membrane, activated PI3K phosphorylates phosphoinosite-2 (PIP2) at position 3 of the inositol to produce PIP3. In addition, Ras, a small GTP-binding protein and potent oncogene, also activates PI3K. PTEN, an important lipid phosphatase and tumor suppressor, dephosphorylates PIP3, counteracting PI3K and decreasing the intensity of the pathway. Accumulation of PIP3 at the plasma membrane recruits several pleckstrin homology domain (PHD)-containing proteins, among them PDK and AKT serine/threonine kinases, which are key components in transducing PI3K signaling. Activated AKTs target different protein substrates for initiation of a biologic response. For example, the Bad protein, phospho-Bad, does not bind Bcl-2 and functions as an antiapoptotic mechanism, promoting cell survival. Other key targets of AKTs are the Forkhead transcription factors (FoxOs) (Fig. 1). When phosphorylated by AKT, phospho-FoxOs are sequestered and inactive in the cytoplasm through direct binding to 14-3-3 proteins. In contrast, dephosphorylated FoxOs activate gene expression associated with stress resistance and cell growth arrest. Another major component downstream of Akt is mammalian target of rapamycin (mTOR, a kinase that belongs to the PI3K-related protein kinase family), which is involved in metabolism, growth, and proliferation. Akt phosphorylates TSC2, which forms a complex with TSC1, decreasing its GTPase-activating protein (GAP) activity for the small GTPase Rheb; as a consequence, the increases in GTP-Rheb activate mTORC1 (one of the mTOR complexes). Among the key downstream targets of mTOR are S6K and 4EBP1, which control protein translation. mTOR can also be activated independently of RTKs through nutrients including branched chain amino acids. mTORC1 forms an amino acid–sensing complex at the lysosomal membranes called the pentameric Ragulator complex that contains Rags, small GTPases that are controlled by the GATOR complex. Interestingly, mTORC1 inhibitors such as rapamycin are used as immunosuppressors in organ transplantation.

Fig1. EXAMPLES OF SIGNALING/TRANSCRIPTIONAL PATH- WAYS PROGRAMMING GENE EXPRESSION

Proteins involved in gene expression are a common target of many signaling pathways, and receptors often stimulate multiple pathways that can regulate common and distinct transcription factors. In the examples shown here, production of PtdIns-3,4,5-P3 by PI3K leads to the activation of the serine/threonine kinase Akt. Akt phosphorylates and inactivates FoxO transcription factors. Ras is activated by the guanine nucleotide exchange factor SOS. Ras activation initiates a cascade of serine/ threonine kinases activity: Ras activates Raf, Raf phosphorylates and activates Mek1, and Mek1 phosphorylates and activates ERK. Phosphorylation of the transcription factor Elk1 by ERK activates gene expression. Increased intra cellular calcium is also a common signaling event. Activation of phospholipase  C leads to hydrolysis of PtdIns-4,5-P2 and production of IP3. IP3 binds to its receptor, leading to intracellular calcium release and then extracellular calcium influx. Calcium activates the serine phosphatase calcineurin, which dephosphorylates NFAT proteins, allowing them to enter the nucleus and stimulate transcription. FoxO, Forkhead transcription factors; IP3, inositol triphosphate; NFAT, nuclear factor of activated T cells; PI3K, phosphatidylinositol 3-kinase; SOS, Son of Sevenless.

MAPK/ERK Pathway

Activated RTKs recruit docking proteins, such as Grb2 and SOS, that allow binding of GTP to Ras to become active and trigger a kinase signaling cascade. Ras activates RAF kinase that, in turn, triggers a series of MEKs, which finally activate MAPK or EEK kinases. ERK phosphorylates many proteins involved in cell growth, including ribosomal S6K, which is involved in protein translation, and AP-1 and c-myc transcription factors, which increase many different cell cycle and antiapoptotic-related genes (see Fig. 1). Other MAPKs include the stress-activated kinases JNK and p38. Constitutive MAPK in hematopoietic stem cells is known to induce myeloproliferative disorders.

اخر الاخبار

اخبار العتبة العباسية المقدسة

أهالي كربلاء يحيون اليوم السابع لذكرى شهادة الإمام الحسين (عليه السلام)

مشروع أمير القراء الوطني يشهد مشاركة أكثر من 100 طالبٍ في مرحلته الثالثة

قسم الشؤون الفكرية يصدر دليلًا يوثّق القصص الفائزة في مسابقة فتوى الدفاع المقدسة

قسم الشؤون الفكرية يعلن عن توفير عددٍ من المكتبات الإلكترونية المتخصّصة للمؤسّسات الدينية والمكتبات العامّة

المزيد

الآخبار الصحية

نصائح عملية للحد من التعرق المفرط في الصيف

أطباء يحذرون: مكمل غذائي شائع قد يدمر الجهاز العصبي

تحذير طبي من تأثير جانبي "غير متوقع" لحقن التخسيس

حمامات الثلج قد تكون خطيرة وأحيانا مميتة.. ما السبب؟

المزيد

الآخبار التكنلوجية

أكبر جدارية شمسية في العالم تدخل موسوعة غينيس.. مشروع ضخم

تسارع دوران الأرض يثير القلق.. وتحذيرات من "كوارث محتملة" ؟

"سوذبيز" تطرح أكبر قطعة من المريخ على الأرض في مزاد علني

أوبن أيه آي تعتزم إطلاق متصفح إنترنت يعمل بالذكاء الاصطناعي

المزيد

مواضيع ذات صلة

Mating Type Conversion in Saccharomyces cerevisiae

The Yeast Cell Cycle

Structure and Function of TFIIIA

Switching from Oocyte to Somatic 5S Synthesis

Genome Editing of Immune Effector Cells for Safer and More Potent Cancer Therapies (CAR-T Cells)

Therapeutic Genome Editing for Hematologic Diseases: β-Thalassemia

Therapeutic Genome Editing for Hematologic Diseases: Sickle Cell Disease

TFIIIA Binding to the Middle of its Gene as Well as to RNA

Biology of 5S RNA Synthesis in Xenopus

Entropy, a Basis for Lambda Repressor Inactivation

Induction from the Lysogenic State

The Need for and the Realization of Hair-Trigger Induction