Abstract:

A feed forward and gate model has been proposed for Fibroblast Growth Factor Receptor-1 (FGFR1), where FGFR1 modulates the extra/intracellular signals that activate transcription. This modulating function would allow FGFR1 to regulate multiple genes and thereby control cell growth and differentiation (1). The model is supported by several publications, but several key questions remain (a)?is cytoplasmic FGFR1 different than nuclear FGFR1, if so how? (b)?what is the mechanism of FGFR1 nuclear entry and is it regulated? and (c)?are FGFR1's nuclear functions regulated, if so how? To address these questions the nuclear functions and cellular dynamics of FGFR1 were investigated.

FGFR1 is located in the membranous, soluble, and nuclear fractions. The membrane bound receptor is released from the ER via secretory vesicles and transported to the Golgi where it undergoes glycosylation. FGFR1 is then release in vesicles to proceed to the plasma membrane for insertion. Soluble FGFR1 is processed in the ER and is either released from the vesicular tubular cluster (VTC) or the early Golgi and subsequently enters the nucleus. Both the soluble and membrane associated FGFR1 populations are full-length, but display distinct dynamics. The nuclear entry of FGFR1 is modulated by protein interactions with RSK1 and FGF2 and the cytoskeleton. Nuclear FGFR1 cooperates with its binding partners to modulate transcription. FGFR1 modulates CREB- and CBP mediated transcription through a direct interaction with CBP and indirectly via protein interactions with RSK1, FGF2, and p85?.

Three different dynamic FGFR1 populations are present within the cytoplasm and nucleus; two distinct mobile populations and an immobile population. The "fast" mobile population has been identified to be the soluble, freely diffusing population of FGFR1 that enters the nucleus. There is also a "slow" population that is associated with membranes, protein complexes, and associated with transcription activation. The immobile population within the cytoplasm is tethered to the cytoskeleton and is speculated to be tethered to the nuclear matrix within the nucleus. Activation of signal transduction pathways and transcription increase FGFR1's dynamics, which is reflected by an increase in protein movement and a decrease in the recovery halftime at which it is moving.