Tristram Hunt is to stand down as MP for Stoke-on-Trent Central to become the director of London's Victoria and Albert Museum.
His resignation means another by-election in a Labour safe seat, weeks after Jamie Reed announced he was quitting as MP for Copeland to take up a post at the Sellafield nuclear plant.
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He added the city would have a "huge place in my heart and in what I do for as long as I live".
The move represents a return to the arts for the Cambridge-educated historian, who was best known for his books and TV programmes before becoming an MP, later serving as shadow secretary for education.
His nomination ahead of the 2010 general election provoked complaints from local party activists, who objected to a London academic with no previous connection to Stoke-on-Trent being "parachuted" into a Labour safe seat. Gary Elsby, the secretary of the local Labour Party, ran as an Independent in protest.
Hunt, however, won with a majority of more than 5,500 and easily retained his seat in 2015, although his 16.7 per cent majority was the constituency's lowest ever. Noting that the unusually low turnout meant less than 19 per cent of Hunt's constituents voted for him, the New Statesman named him the most unpopular MP in Britain.
In 2014, Hunt once again attracted scorn from members of his own party when he crossed a picket line to deliver a lecture at Queen Mary University, London, during a national strike over pay.
The topic of the class was socialism, causing fellow MP Tom Watson to tweet:
However, Watson, now the party's deputy leader, today told the BBC he was "disappointed to see a talented MP like Tristram step down".
A date for the by-election has not yet been announced.