Modulation of lipoprotein receptor functions by intracellular adaptor proteins.
Members of the low density lipoprotein (LDL) receptor gene family are critically involved in a wide range of physiological processes including lipid and vitamin homeostasis, cellular migration, neurodevelopment, and synaptic plasticity, to name a few. Lipoprotein receptors exert these diverse biological functions by acting as cellular uptake receptors or by inducing intracellular signaling cascades. It was discovered that a short sequence in the intracellular region of all lipoprotein receptors, Asn-Pro-X-Tyr (NPXY) is important for mediating either endocytosis or signal transduction events, and that this motif serves as a binding site for phosphotyrosine-binding (PTB) domain containing scaffold proteins. These molecular adaptors connect the transmembrane receptors with the endocytosis machinery and regulate cellular trafficking, or function as assembly sites for dynamic multi-protein signaling complexes. Whereas the LDL receptor represents the archetype of an endocytic lipoprotein receptor, the structurally closely related apolipoprotein E receptor 2 (apoER2) and very low density lipoprotein (VLDL) receptor activate a kinase-dependent intracellular signaling cascade after binding to the neuronal signaling molecule Reelin. This review focuses on two related PTB domain containing adaptor proteins that mediate these divergent lipoprotein receptor responses, ARH (autosomal recessive hypercholesterolemia protein) and Dab1 (disabled-1), and discusses the structural and molecular basis of this different behaviour.
Stolt
Peggy C
PC
Max Planck Institute for Biophysics, Max-von-Laue Str. 3, D-60438 Frankfurt/Main, Germany.
Bock
Hans H
HH
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006801:Humans; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D018110:Receptors, Lipoprotein / Q000737:chemistry / Q000378:metabolism*; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000378:metabolism; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D015816:Cell Adhesion Molecules, Neuronal; C115785:DAB1 protein, human; D016326:Extracellular Matrix Proteins; C469745:LDLRAP1 protein, human; D009419:Nerve Tissue Proteins; D018110:Receptors, Lipoprotein; D000091042:Reelin Protein; C000717127:RELN protein, human; D012697:Serine Endopeptidases