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What are activated Receptor Tyrosine kinases (RTKs)? What is the GTPase Ras and how are Receptor Tyrosine kinases (RTK) involved? What is Akt? I

Answer 1

Activated receptor tyrosine kinases (RTKs) can be described as follows :-

• Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors that transmit the signal for a wide range of molecules like growth factors, cytokines, and hormones.
• When signalling molecules bind to RTKs, they cause neighbouring RTKs to associate with each other.
• This leads to the formation of cross-linked dimers.
• Cross-linking activates the tyrosine kinase activity in these RTKs through phosphorylation — specifically, each RTK in the dimer phosphorylates multiple tyrosine residue on the other RTK. This process is called cross-phosphorylation.
• This leads to the activation of RTKs.
• Once cross-phosphorylated, the cytoplasmic tails of RTKs serve as docking platforms for various intracellular proteins involved in signal transduction. These proteins have a particular domain (called SH2) that bind to phosphorylated tyrosines in the cytoplasmic RTK receptor tails. In this way an activated RTK transmits the signal downstream to it.

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Ras GTPase and RTKs :

• Ras belongs to a family of proteins that are called small GTPase and they are involved in transmitting signals within cells.
• It functions as binary signalling switches with "on" and "off" states. In the "off" state it is bound to the nucleotide guanosine diphosphate (GDP), while in the "on" state, Ras is bound to guanosine triphosphate (GTP), which has an extra phosphate group as compared to GDP.
• Now, RTKs play an important role in activating or switching on Ras.
• As explained in the first part, signalling proteins SH2 domains bind to the tyrosine-phosphorylated residues of the activated RTKs. Now one of these SH2 domain proteins, Grb2, exists in the cytoplasm in a preformed complex with a second protein SOS. SOS can catalyse Ras GTP/GDP exchange.
• After stimulation by the ligand, the tyrosine phosphorylated RTK binds the Grb2/Sos complex, translocating it to the plasma membrane. This translocation is thought to bring Sos into close proximity with Ras, leading to the activation of Ras.
• Ras activation is accelerated by a protein called guanine nucleotide – exchange factor (GEF), which binds to the Ras · GDP complex, causing dissociation of the bound GDP. Because GTP is present in cells at a higher concentration than GDP, GTP binds spontaneously to “empty” Ras molecules, with release of GEF. This is illustrated as follows :-

GDP GTP GEF Ras Antiva GDP Inactive I form GAP GAP | Сате

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What is AKT?

• AKT, also called as protein kinase B (PKB), is a serine/threonine-specific protein kinase that plays an important role in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription and cell migration.
• AKT is majorly known and studied for being involved in the PI3K/AKT/mTOR pathway.
• AKT is activated by PIP3, a phospholipid that is generated by PI3K. In unstimulated cells, PI3K resides in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilises p110 while inhibiting its catalytic activity.
• Upon binding of ligands to RTKs, receptors dimerise and undergo auto-phosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit.
• Activated PI3K IA phosphorylates PIP2, converting it to PIP3. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism.