Receptor Tyrosine Kinases Rtks Proteins

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 Receptor Tyrosine Kinases Rtks Proteins Background

Protein receptor tyrosine kinases (RTKs) are transmembrane-spanning receptors located in the cell membrane that have an intrinsic protein tyrosine kinase activity that is normally dependent on binding of the cognate ligand. There are 58 known RTKs distributed within 20 different families. Each member has a specific biological function; however the different families of RTKs are morphologically related and share a common structure consisting of a large ligand-binding extracellular domain, a lipophilic transmembrane spanning region, and a cytoplasmic domain.

The morphology of the extracellular domain varies between the different type of receptors, and determines the proper recognition and binding to a wide variety of specific ligands. The plasticity of this region is a result of combinations of cysteine-rich motifs, immunoglobulin-like repeats (Ig-like), fibronectin type III repeats (FNIII), and EGF motifs.

The transmembrane domain anchors and stabilizes the receptor in the plasma membrane. It functions as a communication bridge between the extracellular environment and the internal compartments of the cell.

The structure of the cytoplasmic portion is composed of a catalytic tyrosine kinase domain, a juxtamembrane region and a C-terminal tail. Tyrosine kinase domain has the highest level of conservation among tyrosine kinase receptors, and its integrity is essential for adequate receptor signaling. This domain contains an ATP-binding site that catalyzes autophosphorylation of tyrosine residues of the receptor. The juxtamembrane sequence that separates the transmembrane domain and the cytoplasmic domain, is well conserved between members of the same receptor family, although it diverges between different families. This domain acts by modulating the receptor activity under stimuli originating outside the receptor itself, heterologous stimuli (transmodulation) and in some instances, acts as a negative regulator. The most variable region between tyrosine kinase receptors is the C-terminal tail, which contains numerous tyrosine residues that are phosphorylated by the activated kinase.


Functions and mechanisms of activation of Receptor Tyrosine Kinases

RTKs have an important role in mediating the transduction of extracellular signal into the intracellular environment. These signals are involved in a wide range of important cellular processes such as cell growth, cell proliferation, differentiation, and apoptosis. In normal cells, this regulatory activity must be tightly controlled and balanced, sustaining an adequate behavior and function of the cell.

In the absence of a ligand, RTKs are inactive, and presents as a monomeric and unphosphorylated structure. In the state of inactivity, the tyrosine kinase domain has a particular conformation that assures a low catalytic activity of the receptor. Moreover, an interaction between the juxtamembrane and the tyrosine kinase domains has an inhibitory effect to the enzyme, and therefore, helps to sustain a low catalytic condition of the receptor.

The activation of a RTK starts when a growth factor molecule binds to its ligand-binding extracellular domain, which leads to the oligomerization of the receptor with a second monomer receptor. In the dimerized stated, the autoinhibitory activity of the juxtamembrane domain from the receptor is disrupted. Next, a process of transphosphorylation occurs between the two receptors, where each tyrosine kinase domains catalyzes the transfer of γ-phosphate group from adenosine triphosphate (ATP) to tyrosine residues in the C-terminal cytoplasmic tail of the other receptor. In this way, binding sites are generated for signaling proteins that are recruited to the cell membrane, activating a cascade of downstream intracellular signaling pathways. Intracellular mediators transduce those signals through the cytosol and into the nucleus, where the expression of genes is affected. Those genes are involved on a variety of biological processes, including cell growth, migration, differentiation, and cell death.

The receptor oligomerization can occur between two identical receptors (homodimerization), different members of the same receptor family, or in some cases, between a receptor and an accessory protein (heterodimerization). Heterodimerization optimizes the receptor activity by increasing the repertoire of possible ligands recognized by the receptor. The activity of a tyrosine kinase receptor is terminated by phosphatases that hydrolize tyrosil phosphates, and by inhibitory feedback mechanisms induced from downstream pathways.


Deregulation of Receptor Tyrosine Kinases in cancer

Normal cells are constantly under growth-stimulatory signals from their surroundings, which are processed and transmitted internally, and ultimately determine whether cells should growth and divide or not. On the other hand, cancer cells can acquire the ability of sustain proliferative signaling through several mechanisms such as the deregulation of protein tyrosine kinases activity, since they play an important role as regulators of proliferative and survival signal transduction pathways. This is evidenced in the fact that more than 50% of tyrosine kinase receptors have been found to be either overexpressed or mutated in human malignancies.

In comparison to normal cells, cancer cells may greatly exceed the amount of RTKs on their cell membrane. As RTKs can move freely on the cell surface, when present in a higher number, they frequently collide to themselves, causing accidental events of transphosphorylation and consequently, receptor activation. In addition, cancer cells might become more sensitive to the signal from growth factor molecules, and so they can be activated even in the face of a low level of growth factor molecules.

Cancer cells can carry a variety of mutations in RTK-encoding genes, including those that cause amino acids substitutions on the transmembrane domain, or truncations in the ectodomain (gene fusion) and cytoplasmic catalytic domain (particularly ATP-binding motif). RTKs with these forms of mutations are considered oncogenics because they are constitutively dimerized and activated, even in the absence of ligand binding. The dependency of the cell to the continuous signal from transformed kinases is called oncogene addiction, and makes the cancer cell particularly susceptible to the specific kinase inhbitors.

Malignant cells may possess the capability of producing growth factors themselves, to which their receptors can bind and become activated, forming an autostimulatory signaling loop.

Oncogenic mechanisms are often looked as activating factors; however, they can also cause the suppression of normal autoinhibitory and regulatory processes in cancer cells. These negative-feedback mechanisms originating from downstream pathways function to balance intracellular proliferative signaling, and their disruption results in sustained proliferative activity of the cell.