Tristram Hunt is due to step down as the Labour MP for Stoke-on-Trent Central to become the new director of the Victoria and Albert Museum.
The former education secretary, once tipped as a potential future party leader, is the latest Labour MP to step down following Jamie Reed's announcement he will quit for a job in the nuclear industry in December.
A by-election will now be triggered in Stole-on-Trent and will be seen as yet another challenge for the Labour Party, which will have to hold onto a seat that voted to leave the EU by a margin of 81,000 to 36,000 last June.
Hunt managed to hold onto his seat at the 2015 General Election after beating the Ukip candidate Mick Harold by just 5,000 votes.
In his resignation letter, Hunt said he has "no desire to rock the boat" by leaving the party and anyone who interpreters it as such "is just plain wrong".
He described the "extraordinary privilege" of serving in Parliament since 2010 as being "both deeply rewarding and intensely frustrating".
He said: "I am proud of my work in helping to save the Wedgwood Collection, secure tax breaks or the ceramics industry, scrutinise Government policy on the Constitutional Reform Select Committee, and help clean up London's laundering of dirty money on the Criminal Finances Bill.
"It took a while to get there, but I also believe the programme which myself, Kevin Brennan and the shadow education team developed for the 2015 General Election was radical and right.
"Visiting schools and colleges in Stoke and across the country, meeting with teachers and parents and students, allowed me to see the remarkable commitment of English school leaders to their mission as educationalists. But also it highlighted the harrowing effects of poverty and inequality upon social mobility."
Hunt added: "The frustration, of course, came with the inability to address those motors and implement our policy programme following our defeat in 2015 – and, more broadly, about how the Labour Party should respond to the social, cultural and economic forces which have rocked mainstream social democratic and socialist parties from India to Greece to America.
"There were very few jobs that would have convinced me to stand down as MP for Stoke-on-Trent Central, but the post of Director of the V&A – the world's greatest museum of art, design and performance – is just that.
"It brings together all my lifetime passions of education, historical scholarship, meshing past with present and public engagement. It also continues my connection with this wonderful city thanks to the V&A's ownership of the Wedgwood Collection, on show at the Wedgwood Museum in Barlaston."