A Thermodynamic Framework for Understanding RTK Interaction Networks

Receptor tyrosine kinases (RTKs) are the second largest class of membrane proteins, and there are 58 of them in humans divided into 20 subfamilies. They play important roles in many biological processes, including cell growth, differentiation, and division. The prevailing model of RTK activation is that homodimerization allows for autophosphorylation which triggers downstream signaling, although it is appreciated that intra-subfamily heterodimerization can also occur. However, there is growing evidence that many RTKs have inter-subfamily hetero-interactions as well, although there is little understanding of how this affects RTK signaling in general. We demonstrate the commonality of these inter-subfamily hetero-interactions using quantitative FRET spectroscopy. Moreover, we provide a thermodynamic explanation of some of the observed effects of RTK inter-subfamily hetero-interactions and the potential ways such interactions can affect general RTK signaling