Sandbox Reserved 1712

The anaplastic lymphoma kinase was first discovered in 1994 as a tyrosine kinase in a type of lymphoma cancer cell. ALK is a specific type of RTK which plays a huge role in transmembrane signaling and communication within the cell. ALK is commonly expressed in the development of the nervous system. Anaplastic Lymphoma Kinase receptor is a membrane-bound tyrosine kinase. The ALK transfers a phosphate group from ATP to a tyrosine residue on an enzyme which activates a signaling cascade, and ALK becomes activated when a ligand called ALKAL binds to the binding surface on an extracellular domain of ALK. ALK is an integral membrane protein. Abnormal forms of ALK are closely related to the formation of several cancers.

Function

The active state of the kinase is when two monomers have completed a conformational change and moved across the membrane to form a dimer.

Figure 1

Figure 2

^[1]

Fig.1 Anaplastic Lymphoma Kinase and its domains. The region from NTR to the MAM is the Heparin Binding Domain. The TNFL-PXL are the extracellular domains and the EGF is the domain that binds the extracellular region with the extracellular region of the transmembrane. The TMH is the transmembrane domain. The kinase domain is the intracellular portion of the ALK.

Conformational Change

In order for the Anaplastic Lymphoma Kinase (ALK) to move across the membrane to bind with the second monomer, it has to undergo a conformational change. The Anaplastic Lymphoma Kinase Activating Ligand (ALKAL) binds to the binding surface on the ALK. This induces a conformational change which allows for the PXL and the GlyR domains to hinge forward. The kinase is now ready to move across the membrane and attach to the other kinase to be fully activated.

Movement across the membrane

The negatively charged phosphate groups on the cell membrane interact with the highly conserved positively charged residues on ALKAL ligand that face the membrane, which stabilizes the ligand to bind to ALK even better.^[2]

Disease

There are many mutations that could take place causing constitutive receptor activation, enhancement between the interaction of receptors or stabilization of active receptors are known to relate to oncogenic potentials. The histidine residue that is mutated to a arginine is known to be a gain-of-function in lung adenocarcinoma which can lead to constitutive activation of ALK. The phenylalanine residue that is mutated to the a serine may cause a gain-of-function mutation that is linked to acute myeloid leukemia. When the arginine is mutated to a glutamate it is commonly identified in histiocytic neoplasms. The F856S and R753Q mutations are known to increase cytokine-dependent cell proliferation in certain cells.