Research in the Manning Lab

This page covers past research in the Manning lab at the Salk Institute, 2004-2012.

Protein Kinase Evolution

Protein Kinases are one of the largest gene families in eukaryotes, covering about 2% of most eukaryotic proteomes, and with about 60 kinase families shared between most eukaryotes. We study the evolution of protein kinases as a model system for evolution fo genes and gene families, in which we can combine high-throughput approaches with the manual curation that helps us find the many errors and problems of high-throughput work.

Gene Prediction and Orthology Prediction

The errors that we see in automated analyses of kinases cluster into particular categories. Having learned how to fix many errors in kinase annotation, we are now applying these genome-wide. In particular, we are using homology and intron position conservation to improve prediction of gene sequences, and we are using an array of methods to improve the detection of orthologs across eukaryotes.

Protein Phosphatases

Protein phosphatases are the essential counterpart to protein kinases. Mark Chen is working on an indepth analysis of the genomics and evolution of protein phosphatases, similar to our previous work on protein kinases. Mark is also looking at co-evolution of kinases and phosphatases.

Aging and Proteostasis

An emerging field proposes that organismal aging is caused in part by a decline in proteostasis - the cell's ability to keep proteins folded and functional, through chaperones and other mechanisms. Failure of proteostasis may also be a major contributor to neurodegenerative amyloid diseases such as Alzheimer's and Parkinson's, where protein misfolding is a central problem. We are working with the labs of Andy Dillin (Salk), Jeff Kelly, John Yates, and Bill Balch (Scripps) and Elizer Masliah (UCSD) to explore how aging and proteostasis are linked and may affect models of Alzheimer's Disease. A major focus is in three transcriptional responses - to heat shock, insulin signaling, and dietary restriction - that both modulate aging and may affect neurodegeneration. We are using comparative genomics to explore cellular machinery and transcriptional responses across major model organisms.

Protein Secretion, Cystic Fibrosis and Diabetes

We are exploring the sets of proteins that interact with and process secreted proteins in two disease areas, using mass spectrometry and affinity purification. We collaborate with Bill Balch and John Yates on projects surrounding the interactomes of CFTR (the cystic fibrosis transmembrane regulator) and with insulin, to understand their processing, and for CFTR, how drug treaments may help with ensuring proper folding of the mutant protein.


We've worked in the past on a few aspects of metagenomics: one was to use protein sequence similarity to assemble metagenomes and understand their diversity. This was used to explore a new phylum of oceanic archeae in the GOS metagenomic data. We also did massive analysis of domain profiles in that GOS dataset and explored the unexpected diversity of protein kinase-like proteins in prokaryotic genomic and metagenomic data.